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Polyamines and Their Metabolites as Diagnostic Markers of Human Diseases

Polyamines and Their Metabolites as Diagnostic Markers of Human Diseases Polyamines, putrescine, spermidine and spermine, are ubiquitous in living cells and are essential for eukaryotic cell growth. These polycations interact with negatively charged molecules such as DNA, RNA, acidic proteins and phospholipids and modulate vari- ous cellular functions including macromolecular synthesis. Dysregulation of the polyamine pathway leads to pathological condi- tions including cancer, inflammation, stroke, renal failure and diabetes. Increase in polyamines and polyamine synthesis enzymes is often associated with tumor growth, and urinary and plasma contents of polyamines and their metabolites have been investi- gated as diagnostic markers for cancers. Of these, diacetylated derivatives of spermidine and spermine are elevated in the urine of cancer patients and present potential markers for early detection. Enhanced catabolism of cellular polyamines by polyamine oxidases (PAO), spermine oxidase (SMO) or acetylpolyamine oxidase (AcPAO), increases cellular oxidative stress and generates hydrogen peroxide and a reactive toxic metabolite, acrolein, which covalently incorporates into lysine residues of cellular proteins. Levels of protein-conjuagated acrolein (PC-Acro) and polyamine oxidizing enzymes were increased in the locus of brain infarc- tion and in plasma in a mouse model of stroke and also in the plasma of stroke patients. When the combined measurements of PC-Acro, interleukin 6 (IL-6), and C-reactive protein (CRP) were evaluated, even silent brain infarction (SBI) was detected with high sensitivity and specificity. Considering that there are no reliable biochemical markers for early stage of stroke, PC-Acro and PAOs present promising markers. Thus the polyamine metabolites in plasma or urine provide useful tools in early diagnosis of cancer and stroke. Key Words: Polyamine metabolites, Acrolein, Diacetylspemine, Diagnostic marker, Cancer, Stroke INTRODUCTION Thus polyamines engage in stronger and more specific inter - actions with nucleic acids and acidic macromolecules than The polyamines, putrescine [NH (CH ) NH ], spermidine inorganic cations do (Igarashi and Kashiwagi, 2000; Thomas 2 2 4 2 [NH (CH ) NH(CH ) NH ] and spermine [NH (CH ) NH(CH ) and Thomas, 2001; Bachrach, 2005; Igarashi and Kashiwagi, 2 2 4 2 3 2 2 2 3 2 4 NH(CH ) NH ], are organic polycations present in all eukary- 2010). Although net cellular concentrations of polyamines are 2 3 2 otes and are essential for cell proliferation (Tabor and Tabor, generally at millimolar levels in eukaryotic cells (Igarashi and 1984; Igarashi and Kashiwagi, 2010; Pegg and Casero, 2011). Kashiwagi, 2000), most intracellular polyamines are compart- Since their primary and secondary amino groups are protonat- mentalized and/or bound to nucleic acids and other negatively ed at physiological pH, these polyamines interact electrostati- charged molecules. Hence, the concentrations of free poly- cally with negatively charged molecules such as DNA, RNA, amines are much lower than the total cellular concentration. proteins and phospholipids (Bachrach, 2005) and they have Normally, polyamine homeostasis is elaborately maintained been proposed to regulate cellular activities at transcriptional, by intricate multiple feedback mechanisms at the levels of translational and post-translational levels. The polyamines dif- biosynthesis, catabolism, uptake and efflux (Pegg, 2009; Iga - 2+ 2+ fer from inorganic cations like Mg or Ca in that their positive rashi and Kashiwagi, 2010; Pegg and Casero, 2011). Over- charges are spaced at defined distances by flexible methy - accumulation of polyamines has been associated with cell lene chains that can participate in hydrophobic interactions. transformation or apoptosis, whereas their reduction/deple- Open Access http://dx.doi.org/10.4062/biomolther.2012.097 Received Dec 10, 2012 Accepted Jan 4, 2013 This is an Open Access article distributed under the terms of the Creative Com- Corresponding Author mons Attribution Non-Commercial License (http://creativecommons.org/licens- E-mail: [email protected] es/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, Tel: 1-301-496-5056, Fax: 1-301-402-0823 and reproduction in any medium, provided the original work is properly cited. Copyright © 2013 The Korean Society of Applied Pharmacology www.biomolther.org 1 Biomol Ther 21(1), 1-9 (2013) tion leads to inhibition of cell growth, migration, and embryonic arginine by arginase. The rate limiting enzyme in polyamine development. Enhanced levels of polyamines and polyamine biosynthesis is ODC. The polyamine spermidine is synthe- biosynthetic enzymes, ornithine decarboxylase (ODC) and S- sized from putrescine by spermidine synthase, by transfer adenosylmethionine decarboxylase (SAMDC) are often asso- of an aminopropyl moiety from decarboxylated S-adeno- ciated with hyper-proliferation and cancer. NIH3T3 cells over- sylmethionine (DCSAM), to an amino group of putrescine. expressing ODC are tumorigenic in nude mice (Auvinen et Spermine is formed by addition of an aminopropyl moiety at al., 1992) and increased expression of ODC enhances tumor the aminobutyl moiety of spermidine by spermine synthase. development in initiated premalignant epidermal cells (Clifford Spermine and spermidine are converted back to putrescine et al., 1995). Activation of the polyamine catabolic pathway by polyamine oxidases, spermine oxidase (SMO) or acetylpo- causes an increased oxidative stress and also may contrib- lyamine oxidase (AcPAO), a peroxisomal enzyme. Spermine ute to aging and pathological conditions resulting from cellular oxidase oxidatively degrades spermine to spermidine. Alter- damages (Cerrada-Gimenez et al., 2011). natively, spermine and spermidine can be converted to lower polyamines by way of two consecutive enzymatic reactions. First, spermine or spermidine is acetylated at the aminopropyl POLYAMINE METABOLISM IN MAMMALS end by spermidine/spermine N1-acetyltransferase 1 (SSAT1) (Pegg, 2008), a key regulatory enzyme, and the acetylated Cellular polyamines can be interconverted by cycling of spermine and spermidine subsequently undergo oxidative biosynthesis and catabolism and their content is regulated by cleavage between C3 and N4 to generate a lower polyamine. a complex mechanism in mammalian cells (Fig. 1) (Igarashi Alternatively, the monoacetyl-spermine can be acetylated at and Kashiwagi, 2010; Pegg and Casero, 2011). The main the other aminopropyl end to form diacetyl-spermine (Fig. 2). sources for polyamines in mammals are cellular synthesis, The mono- and diacetyl- polyamines can be excreted from food intake and microbial synthesis in the gut. The diamine cells and are detected in cell culture medium, in animal body putrescine is synthesized from ornithine which is formed from fluids, urine and plasma. Polyamine metabolism and regulation in mammalian cells. The biosynthetic enzymes are indicated by yellow ovals, catabolic en- Fig. 1. zymes in aquablue ovals, and hypusine modification enzymes in green ovals. Inhibition is indicated by broken red lines and stimulation by solid blue lines. ODC: ornithine decarboxylase; SAMDC: S-adenosylmethionine decarboxylase; SPDS: spermidine synthase; SPMS: spermine synthase, SSAT1: spermidine/spermine N -acetyltransferase; AcPAO: acetylpolyamine oxidase; SMO: spermine oxidase; eIF5A: eukaryotic initiation factor 5A; eIF5A (Lys): eIF5A lysine form; eIF5A (Dhp): eIF5A deoxyhypusine form; eIF5A (Hpu): eIF5A hypusine form; DHS: deoxyhypusine synthase; DOHH: deoxyhypusine hydroxylase; Az: antizyme; AzI: antizyme inhibitor. http://dx.doi.org/10.4062/biomolther.2012.097 2 Park and Igarashi. Polyamine Metabolites as Markers of Cancer and Stroke Generation of acrolein and protein-conjugated acrolein by polyamine oxidase reactions. Acrolein generated by SMO, AcPAO or Fig. 2. BSAO reacts with e-amino group of lysine residues of proteins to form FDP-lysine containing adducts. BSAO: bovine serum amine oxidase; FDP-Lys: N-(3-formyl-3,4-dehydropiperidino)lysine. Polyamine oxidase (SMO or AcPAO) mediated reactions zymes, ODC, SAMDC and SSAT1 are highly regulated by cause oxidative stress to cells and tissues. In addition to a polyamines and by various stimuli such as growth factors, lower polyamine, SMO generates H O and 3-aminopropa- hormones, 12-O-tetradecanoylphorbol-1 3-acetate (TPA), etc 2 2 nal and AcPAO generates H O and 3-acetylaminopropanal (Pegg, 2009). In the presence of high levels of spermidine and 2 2 (Fig. 2). These aldehydes are unstable and spontaneously spermine in cells or medium, ODC and SAMDC are down- decompose to acrolein after deamination. Acrolein can be regulated while SSAT1 is upregulated. Reciprocally, when also generated extracellularly from spermine or spermidine in cellular polyamine levels are reduced, ODC and SAMDC are cell culture medium containing bovine serum amine oxidase upregulated and SSAT1 is downregulated. The regulation (BSAO) -like activity that oxidizes at the terminal amino group occurs at the transcriptional, translational, and posttransla- of polyamines (Sharmin et al., 2001). Acrolein, an unsaturated tional levels and specific mechanisms of regulation of these reactive aldehyde, is highly toxic and readily reacts with lysine enzymes by polyamines have been extensively investigated residues of proteins to form N -(3-formyl-3,4-dehydropiperidi- (Pegg, 2009; Igarashi and Kashiwagi, 2010). When the cel- no)lysine (FDP-lysine) (Uchida et al., 1998). lular polyamine level increases, ODC is downregulated by in- In addition to the polyamine interconversion pathway, a duction of antizyme (Az) translation by frame shifting (Ivanov small amount of cellular spermidine is covalently incorporat- et al., 1998; Coffino, 2001). The antizyme forms a complex ed into a specific cellular protein eIF5A to form an unusual with the ODC monomer to inactivate the enzyme and directs it amino acid hypusine [N -(4-amino-2-hydroxybutyl)lysine] to degradation by the 26S proteasome. In addition, antizyme (Fig.1) (Park, 2006; Park et al., 2010). The first step enzyme, inhibits polyamine uptake and stimulates its secretion. Further deoxyhypusine synthase (DHS) (Joe et al., 1995) catalyzes complexity of ODC regulation is introduced by an antizyme in- the NAD-dependent cleavage of spermidine between N4 hibitor (AzI) (Fujita et al., 1982), which shares high sequence and C5 and the transfer of aminobutyl moiety of spermidine similarity to ODC, but is devoid of the enzyme activity. to the e-amino-group of a specific lysine residue of the eIF5A precursor, eIF5A(Lys), to form a deoxyhypusine-containing intermediate, eIF5A(Dhp). This intermediate is subsequently PROPOSED FUNCTIONS OF POLYAMINES hydroxylated by deoxyhypusine hydroxylase (DOHH) (Park et al., 2006) to form hypusine and the biologically active, mature From gene disruption studies in yeast and mice (Jänne et eIF5A, eIF5A(Hpu). al., 2004), it is well established that polyamines are essen- The polyamine biosynthetic enzymes and catabolic en- tial for eukaryotic cell growth and mammalian development www.biomolther.org 3 Biomol Ther 21(1), 1-9 (2013) (Pegg, 2009). As mentioned above (Fig. 1), one well defined response element in the promoter region (for SSAT1) (Wang function of polyamine is the requirement for spermidine for hy- et al., 1998). pusine modification in eIF5A (Park, 2006; Park et al., 2010). In addition, polyamines have been proposed to play several Since eIF5A and its deoxyhypusine/hypusine modification are other important roles in cellular regulation and animal physiol- essential for eukaryotic cell growth and mouse development ogy (Pegg, 2009; Minois et al., 2011). Due to their interaction (Nishimura et al., 2012), the eIF5A modification defines one with DNA structure (Thomas and Thomas, 2001), their effects specific function of polyamines. Due to a narrow specificity on chromatin condensation (Matthews, 1993) and enzymes of DHS for spermidine, only natural polyamine or an analog such as HAT and HDAC (Hobbs et al., 2002) and protein ki- with closely related structure to spermidine can support long- nases/phosphatases (Lawson et al., 2005), polyamines may term growth of mammalian cells (Byers et al., 1994; Hyvönen also regulate transcription and gene expression, directly or et al., 2007). In addition to eIF5A modification, polycationic indirectly. The two oncogenes, c-Myc and c-Jun were reported polyamines are also essential for proliferation of mammalian to be transcriptionally controlled by polyamines in cells treated cells (Nishimura et al., 2005). These organic polycations fulfill with DFMO (Patel and Wang, 1997). The polyamine effects unique cellular functions that cannot be substituted by inor- on global transcription have been investigated by microarray 2+ ganic cations, such as Mg in macromolecular synthesis or in analyses in mammalian cells partially depleted of polyamine cell growth (Oredsson et al., 1984). Numerous studies have by treatment with DFMO (Landau et al., 2012). been reported on the effects of polyamines on DNA structure Polyamines also bind and regulate glutamate receptor ion (Thomas and Thomas, 2001), chromatin condensation (Mat- channels (Dingledine et al., 1999), inwardly rectifying potas- thews, 1993), RNA structure (Igarashi and Kashiwagi, 2010) sium channels (Kir) (Stanfield and Sutcliffe, 2003), and oth - and protein synthesis in vitro (Ogasawara et al., 1989). How- er channels that affect intracellular calcium signaling or Na ever, the molecular mechanism of polycationic polyamine ac- transport (Fleidervish et al., 2008). Although spermine is not tions in vivo has remained obscure for decades. required for mammalian cell growth, spermine synthase de- Insights on the cellular function of polyamines in protein fective mice (Gy mice) are totally deaf (Wang et al., 2009), synthesis have been offered by their cellular distribution, es- suggesting the importance of homeostasis of spermidine and timated from the individual dissociation constant for each of spermine in animal development and physiology. polyamine-partner binding under the physiological concentra- + 2+ tions of K and Mg of E. coli and mammalian cells (Igarashi and Kashiwagi, 2010). In mammalian cells and tissues, a ma- POLYAMINES, AGING AND HUMAN DISEASES jority of cellular spermidine and spermine (57-85%) appear to be bound to RNA, whereas free polyamines and the fractions Since polyamines are essential for cell growth and viability bound to other components (DNA, ATP or phospholipids) are (Pendeville et al., 2001; Nishimura et al., 2002), polyamine relatively small. Furthermore, the crystal structure of yeast levels change with aging, and under several disease condi- Phe tRNA revealed two molecules of spermine (Quigley et al., tions (Minois et al., 2011). Decrease in polyamines with aging 1978), suggesting specific interactions between polyamines was evaluated with mouse (Nishimura et al., 2006), and the and RNA. In in vitro translation assays, polyamines not only decrease in polyamine content was observed in almost all tis- 2+ lowered the Mg requirement, but also stimulated protein sues, and it was especially notable in skin, heart and muscle. 2+ synthesis beyond the maximum level achieved by high Mg The decrease was not significant in brain and pancreas. It also alone (Ogasawara et al., 1989). In addition, polyamines were became clear that polyamine-rich food decreases mortality in reported to exert several other effects on translation, including aged mice (Soda et al., 2009). stimulation of the assembly of the 30S ribosome, rat liver Ile- Deregulation of the polyamine pathway enzymes has been tRNA formation, an increase in the fidelity of protein synthesis implicated in various pathological conditions, including cancer and frame shifting (Igarashi and Kashiwagi, 2010). (Gerner and Meyskens, 2004; Casero and Marton, 2007), in- More recently, further evidence for a primary function of flammation (Babbar et al., 2007), stroke (Tomitori et al., 2005; polyamines in translation was obtained in mammalian cells Yoshida et al., 2010; Igarashi and Kashiwagi, 2011b; Saiki et over-expressing SSAT1. Rapid arrest in protein synthesis and al., 2011), renal failure (Igarashi et al., 2006) and diabetes cell growth occurred in these cells depleted of spermidine and (Kramer et al., 2008). spermine by SSAT1 over-expression, whereas there was little As for cancer, Russell and Snyder first reported high levels or no inhibition of synthesis of DNA and RNA (Mandal et al., of ODC activity in regenerating rat liver and in several human 2013). These findings are consistent with specific interactions cancers (Russell and Snyder, 1968). Since then, effects of in- of polyamines with RNA (Igarashi and Kashiwagi, 2010), and hibitors of polyamine biosynthesis; i.e., a-difluoromethylorni - their stimulatory effects on protein synthesis in vitro (Ogas- thine (DFMO) (Mamont et al., 1978), an inhibitor of ODC, and awara et al., 1989), and corroborate an important function of methylglyoxal bis(guanylhaydrazone) (MGBG) (Williams-Ash- the polyamines spermidine and spermine in translation. Thus, man and Schenone, 1972), an inhibitor of SAMDC, on cancer polyamines appear to contribute to mammalian cell growth growth were extensively studied with mice bearing various mainly through their participation in eIF5A hypusine modifica - cancers. The combination of DFMO-MGBG has been shown tion (Park, 2006) and by stimulating translation initiation by to be more effective therapeutically than either drug alone in enhancing ribosome assembly and stability (Ogasawara et a number of in vivo model systems, which include Ehrlich as- al., 1989). Specific genes influenced by cellular polyamines at cites carcinoma (Seppänen et al., 1983), murine L1210 and translation include Az, SAMDC, and SSAT1 and their regula- P388 leukemia (Kramer et al., 1985; Nakaike et al., 1988), tion involves different mechanisms, including ribosome frame and murine renal adenocarcinoma (Herr et al., 1984). Further- shifting (for Az) (Ivanov et al., 1998), a small upstream open more, the stronger antitumor effects were exerted when mice reading frame (for SAMDC) (Mize et al., 1998), and polyamine were fed a polyamine-deficient diet (Nakaike et al., 1988), http://dx.doi.org/10.4062/biomolther.2012.097 4 Biomol Ther 21(1), 1-9 (2013) al., 2007), and second, an unsaturated aldehyde such as ac- rolein (Stevens and Maier, 2008). Addition of SPD and SPM to culture medium containing ruminant serum causes inhibi- tion of cell proliferation (Higgins et al., 1969; Agostinelli et al., 2010). This effect is caused by oxidation products of the poly- amines by ruminant amine oxidase, H O and acrolein (Fig. 2 2 2). In a cell culture system, complete inhibition of cell growth was accomplished with 10 mM acrolein, 100 mM H O and 20 2 2 mM hydroxylradical produced by 20 mM H O and 1 mM Vita- 2 2 min C (Yoshida et al., 2009), suggesting acrolein as the major toxic agent. These findings led us to test whether acrolein or protein-conjugated acrolein (PC-Acro) is a good biochemical marker for stroke and chronic renal failure. At present, there is no reliable biochemical marker for diag- nosis of the early stage of stroke. Thus, the activities of sperm- ine oxidase (SMO) and acetylpolyamine oxidase (AcPAO) were measured along with the level of PC-Acro in plasma of patients with stroke (Tomitori et al., 2005). PC-Acro was metowardasured by ELISA using anti-FDP-lysine antibody (Uchida et al., 1998). The median levels of PC-Acro and to- tal polyamine oxidases (SMO and AcPAO) were significantly higher in the plasma of patients with stroke. The median lev- els of PC-Acro and total polyamine oxidase activity (PAO) in plasma increased from 14.4 to 21.3 nmol/ml plasma and from 4.5 to 8.0 nmol SPD produced from SPM by PAO/ml plasma, respectively. It was then examined whether the increases in PC-Acro and PAO are correlated with the severity of stroke (size of the infarct). Because the maximal increase in PAO precedes that in PC-Acro, the multiplied value of PAO by PC- Acro was compared with the size of the infarct. Statistical significance between stroke patients and no-stroke subjects −7 became greater in the multiplied value (p=9.3×10 ) than PAO −5 −6 (p=7.0×10 ) or PC-Acro (p=6.6×10 ). The size of the infarct was nearly parallel with the value of PAO activity multiplied by PC-Acro amount (Tomitori et al., 2005). Correlation between brain infarction and PC-Acro in PIT Fig. 3. There are reports that silent brain infarction (SBI) increases model mice. (A) Infarction volume at 24 h after the induction of infarction, the level of PC-Acro estimated by Western blotting us- the risk of subsequent stroke (Vermeer et al., 2007), dementia ing anti-FDP-Lys antibody, and polyamine levels at the locus of (Vermeer et al., 2007), and mild cognitive impairment (Lopez brain infarction and at the corresponding locus in normal mice et al., 2003). Furthermore, it has been reported that carotid are shown. (B) Increase in PC-Acro and polyamines in plasma of atherosclerosis (CA) is a risk factor for stroke and SBI (In- PIT model mice with brain infarction is shown. *p<0.05, **p<0.01, oue et al., 2007), and that SBI and white matter hyperintensity ***p<0.001. Data were adapted from Saiki et al. (2009). (WMH) increase the risk for stroke and mortality (Bokura et al., 2006). Thus, it was tested how PC-Acro is correlated with SBI, WMH and CA by collecting blood from 790 elderly healthy volunteers. Since the levels of CRP and IL-6 are reported to lyzed together with age as a factor. The median RRV (relative increase in the serum of apparently healthy individuals with risk value) for SBI with CA (93 subjects), SBI (214 subjects), SBI (Hoshi et al., 2005), the levels of CRP and IL-6 were mea- CA (263 subjects), WMH with CA (90 subjects), WMH (245 sured along with PC-Acro (Yoshida et al., 2010). SBI (affected subjects) and control (260 subjects) was 0.90, 0.80, 0.76, areas ≥3 mm diameter) and WMH were estimated by MRI, 0.65, 0.46 and 0.14, respectively. Although PC-Acro is well CA by carotid ultrasound examination, and CRP and IL-6 in correlated with brain infarction, measurement of IL-6 and CRP plasma by ELISA. PC-Acro, IL-6 and CRP were significantly along with PC-Acro was necessary to increase sensitivity and higher in SBI and CA compared with the control. PC-Acro was specificity to detect SBI. most strongly correlated with CA, and IL-6 and CRP with SBI The role of PC-Acro and polyamine oxidases was also (Yoshida et al., 2010). Thus, CA is likely the primary risk factor evaluated in an animal model of stroke by using photochemi- related to stroke in this analysis. cally induced thrombosis (PIT) model mice (Fig. 3) (Saiki et It was next determined whether SBI, CA and WMH could be al., 2009). In this model, it was determined whether acrolein detected by altered levels of PC-Acro, IL-6 and CRP using a is produced from polyamines at the locus of infarction. The receiver operating characteristic (ROC) curve – a commonly volume of infarcted tissue was determined by staining 2-mm- used technique for assessing diagnostic and predictive accu- thick coronal slices with triphenyltetrazolium, which stains the racy in disease management (Linden, 2006). Since age was viable brain tissue red whereas infarcted tissue remains un- an important factor among various markers evaluated for the stained. The average volume of infarction at 24 h of PIT model detection of SBI, CA and WMH, these three values were ana- mice was 23 mm (Fig. 3A). The PC-Acro determined by west- http://dx.doi.org/10.4062/biomolther.2012.097 6 Biomol Ther 21(1), 1-9 (2013) duplication and keratosis follicularis spinulosa decalvans (KFSD). Biochem. 139, 315-322. Hum. Genet. 111, 235-241. Kramer, D. L., Diegelman, P., Jell, J., Vujcic, S., Merali, S. and Porter, Giorgio, M., Trinei, M., Migliaccio, E. and Pelicci, P. G. (2007) Hydro- C. W. (2008) Polyamine acetylation modulates polyamine meta- gen peroxide: a metabolic by-product or a common mediator of bolic flux, a prelude to broader metabolic consequences. J. Biol. ageing signals? Nat. Rev. Mol. Cell Biol. 8, 722-728. Chem. 283, 4241-4251. Gomez, M. and Hellstrand, P. (1995) Effects of polyamines on voltage- Kramer, D. L., Paul, B. and Porter, C. W. (1985) Effect of pretreatment activated calcium channels in guinea-pig intestinal smooth muscle. with alpha-difluoromethylornithine on the selectivity of methylglyox - Pflugers Arch. 430, 501-507. al bis(guanylhydrazone) for tumor tissue in L1210 leukemic mice. Herr, H. W., Kleinert, E. L., Conti, P. S., Burchenal, J. H. and Whitmore, Cancer Res. 45, 2512-2515. W.F., Jr. (1984) Effects of alpha-difluoromethylornithine and meth - Landau, G., Ran, A., Bercovich, Z., Feldmesser, E., Horn-Saban, S., ylglyoxal bis(guanylhydrazone) on the growth of experimental renal Korkotian, E., Jacob-Hirsh, J., Rechavi, G., Ron, D. and Kahana, adenocarcinoma in mice. Cancer Res. 44, 4382-4385. C. (2012) Expression profiling and biochemical analysis suggest Higgins, M. L., Tillman, M. C., Rupp, J. P. and Leach, F. R. (1969) stress response as a potential mechanism inhibiting proliferation of The effect of polyamines on cell culture cells. J. Cell. Physiol. 74, polyamine-depleted cells. J. Biol. Chem. 287, 35825-35837. 149-154. Lawson, K., Larentowicz, L., Laury-Kleintop, L. and Gilmour, S. K. Hiramatsu, K., Takahashi, K., Yamaguchi, T., Matsumoto, H., Miyamo- (2005) B23 is a downstream target of polyamine-modulated CK2. to, H., Tanaka, S., Tanaka, C., Tamamori, Y., Imajo, M., Kawaguchi, Mol. Cell. Biochem. 274, 103-114. 1 12 M. et al. (2005) N( ),N( )-Diacetylspermine as a sensitive and spe- Linden, A. (2006) Measuring diagnostic and predictive accuracy in dis- cific novel marker for early- and late-stage colorectal and breast ease management: an introduction to receiver operating character- cancers. Clin. Cancer Res. 11, 2986-2990. istic (ROC) analysis. J. Eval. Clin. Pract. 12, 132-139. Hobbs, C. A., Paul, B. A. and Gilmour, S. K. (2002) Deregulation of Lopez, O. L., Jagust, W. J., Dulberg, C., Becker, J. T., DeKosky, S. T., polyamine biosynthesis alters intrinsic histone acetyltransferase Fitzpatrick, A., Breitner, J., Lyketsos, C., Jones, B., Kawas, C. et and deacetylase activities in murine skin and tumors. Cancer Res. al. (2003) Risk factors for mild cognitive impairment in the Cardio- 62, 67-74. vascular Health Study Cognition Study: part 2. Arch. Neurol. 60, Hoshi, T., Kitagawa, K., Yamagami, H., Furukado, S., Hougaku, H. and 1394-1399. Hori, M. (2005) Relations of serum high-sensitivity C-reactive pro- Mamont, P. S., Duchesne, M. C., Grove, J. and Bey, P. (1978) Anti- tein and interleukin-6 levels with silent brain infarction. Stroke 36, proliferative properties of DL-alpha-difluoromethyl ornithine in cul - 768-772. tured cells. A consequence of the irreversible inhibition of ornithine Hyvönen, M. T., Keinanen, T. A., Cerrada-Gimenez, M., Sinervirta, R., decarboxylase. Biochem. Biophys. Res. Commun. 81, 58-66. Grigorenko, N., Khomutov, A. R., Vepsalainen, J., Alhonen, L. and Mandal, S., Mandal, A., Johansson, H. E., Orjalo, A. V. and Park, M. H. Janne, J. (2007) Role of hypusinated eukaryotic translation initia- (2013) Depletion of cellular polyamines, spermidine and spermine, tion factor 5A in polyamine depletion-induced cytostasis. J. Biol. causes a total arrest in translation and growth in mammalian cells. Chem. 282, 34700-34706. Proc. Natl. Acad. Sci. USA in press published ahead of print Janu- Igarashi, K. and Kashiwagi, K. (2000) Polyamines: mysterious modula- ary 23, 2013, doi:10.1073/pnas.1219002110 tors of cellular functions. Biochem. Biophys. Res. Commun. 271, Matthews, H. R. (1993) Polyamines, chromatin structure and transcrip- 559-564. tion. Bioessays 15, 561-566. Igarashi, K. and Kashiwagi, K. (2010) Modulation of cellular function by Minois, N., Carmona-Gutierrez, D. and Madeo, F. (2011) Polyamines polyamines. Int. J. Biochem. Cell Biol. 42, 39-51. in aging and disease. Aging (Albany NY) 3, 716-732. Igarashi, K. and Kashiwagi, K. (2011a) Use of polyamine metabolites Mize, G. J., Ruan, H., Low, J. J. and Morris, D. R. (1998) The inhibitory as markers for stroke and renal failure. Methods Mol. Biol. 720, upstream open reading frame from mammalian S-adenosylmethio- 395-408. nine decarboxylase mRNA has a strict sequence specificity in criti - Igarashi, K. and Kashiwagi, K. (2011b) Protein-conjugated acrolein as cal positions. J. Biol. Chem. 273, 32500-32505. a biochemical marker of brain infarction. Mol. Nutr. Food Res. 55, Nakaike, S., Kashiwagi, K., Terao, K., Iio, K. and Igarashi, K. (1988) 1332-1341. Combined use of alpha-difluoromethylornithine and an inhibitor of Igarashi, K., Ueda, S., Yoshida, K. and Kashiwagi, K. (2006) Poly- S-adenosylmethionine decarboxylase in mice bearing P388 leuke- amines in renal failure. Amino Acids 31, 477-483. mia or Lewis lung carcinoma. Jpn. J. Cancer Res. 79, 501-508. Inoue, K., Matsumoto, M., Shono, T., Toyokawa, S. and Moriki, A. Nishimura, K., Lee, S. B., Park, J. H. and Park, M. H. (2012) Essential (2007) Increased intima media thickness and atherosclerotic role of eIF5A-1 and deoxyhypusine synthase in mouse embryonic plaques in the carotid artery as risk factors for silent brain infarcts. development. Amino Acids 42, 703-710. J. Stroke Cerebrovasc. Dis. 16, 14-20. Nishimura, K., Murozumi, K., Shirahata, A., Park, M. H., Kashiwagi, K. Ivanov, I. P., Gesteland, R. F., Matsufuji, S. and Atkins, J. F. (1998) Pro- and Igarashi, K. (2005) Independent roles of eIF5A and polyamines grammed frameshifting in the synthesis of mammalian antizyme is in cell proliferation. Biochem. J. 385, 779-785. +1 in mammals, predominantly +1 in fission yeast, but -2 in bud - Nishimura, K., Nakatsu, F., Kashiwagi, K., Ohno, H., Saito, T. and Iga- ding yeast. RNA 4, 1230-1238. rashi, K. (2002) Essential role of S-adenosylmethionine decarbox- Jänne, J., Alhonen, L., Pietila, M. and Keinanen, T. A. (2004) Genetic ylase in mouse embryonic development. Genes Cells 7, 41-47. approaches to the cellular functions of polyamines in mammals. Nishimura, K., Shiina, R., Kashiwagi, K. and Igarashi, K. (2006) De- Eur. J. Biochem. 271, 877-894. crease in polyamines with aging and their ingestion from food and Jin, L., Miyazaki, M., Mizuno, S., Takigawa, M., Hirose, T., Nishimura, drink. J. Biochem. 139, 81-90. K., Toida, T., Williams, K., Kashiwagi, K. and Igarashi, K. (2008) Ogasawara, T., Ito, K. and Igarashi, K. (1989) Effect of polyamines The pore region of N-methyl-D-aspartate receptors differentially on globin synthesis in a rabbit reticulocyte polyamine-free protein influences stimulation and block by spermine. J. Pharmacol. Exp. synthetic system. J. Biochem. 105, 164-167. Ther. 327, 68-77. Oredsson, S. M., Alm, K., Dahlberg, E., Holst, C. M., Johansson, V. M., Joe, Y. A., Wolff, E. C. and Park, M. H. (1995) Cloning and expres- Myhre, L. and Soderstjerna, E. (2007) Inhibition of cell proliferation sion of human deoxyhypusine synthase cDNA. Structure-function and induction of apoptosis by N1,N11-diethylnorspermine-induced studies with the recombinant enzyme and mutant proteins. J. Biol. polyamine pool reduction. Biochem. Soc. Trans. 35, 405-409. Chem. 270, 22386-22392. Oredsson, S. M., Anehus, S. and Heby, O. (1984) Reversal of the Kaasinen, S. K., Oksman, M., Alhonen, L., Tanila, H. and Janne, J. growth inhibitory effect of alpha-difluoromethylornithine by putres - (2004) Spermidine/spermine N1-acetyltransferase overexpression cine but not by other divalent cations. Mol. Cell. Biochem. 64, 163- in mice induces hypoactivity and spatial learning impairment. Phar- 172. macol. Biochem. Behav. 78, 35-45. Park, J. H., Aravind, L., Wolff, E. C., Kaevel, J., Kim, Y. S. and Park, M. Kawakita, M. and Hiramatsu, K. (2006) Diacetylated derivatives of H. (2006) Molecular cloning, expression, and structural prediction spermine and spermidine as novel promising tumor markers. J. of deoxyhypusine hydroxylase: a HEAT-repeat-containing metallo- http://dx.doi.org/10.4062/biomolther.2012.097 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Biomolecules & Therapeutics Pubmed Central

Polyamines and Their Metabolites as Diagnostic Markers of Human Diseases

Park, Myung Hee; Igarashi, Kazuei
Biomolecules & Therapeutics , Volume 21 (1) – Jan 1, 2013
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Abstract

Polyamines, putrescine, spermidine and spermine, are ubiquitous in living cells and are essential for eukaryotic cell growth. These polycations interact with negatively charged molecules such as DNA, RNA, acidic proteins and phospholipids and modulate vari- ous cellular functions including macromolecular synthesis. Dysregulation of the polyamine pathway leads to pathological condi- tions including cancer, inflammation, stroke, renal failure and diabetes. Increase in polyamines and polyamine synthesis enzymes is often associated with tumor growth, and urinary and plasma contents of polyamines and their metabolites have been investi- gated as diagnostic markers for cancers. Of these, diacetylated derivatives of spermidine and spermine are elevated in the urine of cancer patients and present potential markers for early detection. Enhanced catabolism of cellular polyamines by polyamine oxidases (PAO), spermine oxidase (SMO) or acetylpolyamine oxidase (AcPAO), increases cellular oxidative stress and generates hydrogen peroxide and a reactive toxic metabolite, acrolein, which covalently incorporates into lysine residues of cellular proteins. Levels of protein-conjuagated acrolein (PC-Acro) and polyamine oxidizing enzymes were increased in the locus of brain infarc- tion and in plasma in a mouse model of stroke and also in the plasma of stroke patients. When the combined measurements of PC-Acro, interleukin 6 (IL-6), and C-reactive protein (CRP) were evaluated, even silent brain infarction (SBI) was detected with high sensitivity and specificity. Considering that there are no reliable biochemical markers for early stage of stroke, PC-Acro and PAOs present promising markers. Thus the polyamine metabolites in plasma or urine provide useful tools in early diagnosis of cancer and stroke. Key Words: Polyamine metabolites, Acrolein, Diacetylspemine, Diagnostic marker, Cancer, Stroke INTRODUCTION Thus polyamines engage in stronger and more specific inter - actions with nucleic acids and acidic macromolecules than The polyamines, putrescine [NH (CH ) NH ], spermidine inorganic cations do (Igarashi and Kashiwagi, 2000; Thomas 2 2 4 2 [NH (CH ) NH(CH ) NH ] and spermine [NH (CH ) NH(CH ) and Thomas, 2001; Bachrach, 2005; Igarashi and Kashiwagi, 2 2 4 2 3 2 2 2 3 2 4 NH(CH ) NH ], are organic polycations present in all eukary- 2010). Although net cellular concentrations of polyamines are 2 3 2 otes and are essential for cell proliferation (Tabor and Tabor, generally at millimolar levels in eukaryotic cells (Igarashi and 1984; Igarashi and Kashiwagi, 2010; Pegg and Casero, 2011). Kashiwagi, 2000), most intracellular polyamines are compart- Since their primary and secondary amino groups are protonat- mentalized and/or bound to nucleic acids and other negatively ed at physiological pH, these polyamines interact electrostati- charged molecules. Hence, the concentrations of free poly- cally with negatively charged molecules such as DNA, RNA, amines are much lower than the total cellular concentration. proteins and phospholipids (Bachrach, 2005) and they have Normally, polyamine homeostasis is elaborately maintained been proposed to regulate cellular activities at transcriptional, by intricate multiple feedback mechanisms at the levels of translational and post-translational levels. The polyamines dif- biosynthesis, catabolism, uptake and efflux (Pegg, 2009; Iga - 2+ 2+ fer from inorganic cations like Mg or Ca in that their positive rashi and Kashiwagi, 2010; Pegg and Casero, 2011). Over- charges are spaced at defined distances by flexible methy - accumulation of polyamines has been associated with cell lene chains that can participate in hydrophobic interactions. transformation or apoptosis, whereas their reduction/deple- Open Access http://dx.doi.org/10.4062/biomolther.2012.097 Received Dec 10, 2012 Accepted Jan 4, 2013 This is an Open Access article distributed under the terms of the Creative Com- Corresponding Author mons Attribution Non-Commercial License (http://creativecommons.org/licens- E-mail: [email protected] es/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, Tel: 1-301-496-5056, Fax: 1-301-402-0823 and reproduction in any medium, provided the original work is properly cited. Copyright © 2013 The Korean Society of Applied Pharmacology www.biomolther.org 1 Biomol Ther 21(1), 1-9 (2013) tion leads to inhibition of cell growth, migration, and embryonic arginine by arginase. The rate limiting enzyme in polyamine development. Enhanced levels of polyamines and polyamine biosynthesis is ODC. The polyamine spermidine is synthe- biosynthetic enzymes, ornithine decarboxylase (ODC) and S- sized from putrescine by spermidine synthase, by transfer adenosylmethionine decarboxylase (SAMDC) are often asso- of an aminopropyl moiety from decarboxylated S-adeno- ciated with hyper-proliferation and cancer. NIH3T3 cells over- sylmethionine (DCSAM), to an amino group of putrescine. expressing ODC are tumorigenic in nude mice (Auvinen et Spermine is formed by addition of an aminopropyl moiety at al., 1992) and increased expression of ODC enhances tumor the aminobutyl moiety of spermidine by spermine synthase. development in initiated premalignant epidermal cells (Clifford Spermine and spermidine are converted back to putrescine et al., 1995). Activation of the polyamine catabolic pathway by polyamine oxidases, spermine oxidase (SMO) or acetylpo- causes an increased oxidative stress and also may contrib- lyamine oxidase (AcPAO), a peroxisomal enzyme. Spermine ute to aging and pathological conditions resulting from cellular oxidase oxidatively degrades spermine to spermidine. Alter- damages (Cerrada-Gimenez et al., 2011). natively, spermine and spermidine can be converted to lower polyamines by way of two consecutive enzymatic reactions. First, spermine or spermidine is acetylated at the aminopropyl POLYAMINE METABOLISM IN MAMMALS end by spermidine/spermine N1-acetyltransferase 1 (SSAT1) (Pegg, 2008), a key regulatory enzyme, and the acetylated Cellular polyamines can be interconverted by cycling of spermine and spermidine subsequently undergo oxidative biosynthesis and catabolism and their content is regulated by cleavage between C3 and N4 to generate a lower polyamine. a complex mechanism in mammalian cells (Fig. 1) (Igarashi Alternatively, the monoacetyl-spermine can be acetylated at and Kashiwagi, 2010; Pegg and Casero, 2011). The main the other aminopropyl end to form diacetyl-spermine (Fig. 2). sources for polyamines in mammals are cellular synthesis, The mono- and diacetyl- polyamines can be excreted from food intake and microbial synthesis in the gut. The diamine cells and are detected in cell culture medium, in animal body putrescine is synthesized from ornithine which is formed from fluids, urine and plasma. Polyamine metabolism and regulation in mammalian cells. The biosynthetic enzymes are indicated by yellow ovals, catabolic en- Fig. 1. zymes in aquablue ovals, and hypusine modification enzymes in green ovals. Inhibition is indicated by broken red lines and stimulation by solid blue lines. ODC: ornithine decarboxylase; SAMDC: S-adenosylmethionine decarboxylase; SPDS: spermidine synthase; SPMS: spermine synthase, SSAT1: spermidine/spermine N -acetyltransferase; AcPAO: acetylpolyamine oxidase; SMO: spermine oxidase; eIF5A: eukaryotic initiation factor 5A; eIF5A (Lys): eIF5A lysine form; eIF5A (Dhp): eIF5A deoxyhypusine form; eIF5A (Hpu): eIF5A hypusine form; DHS: deoxyhypusine synthase; DOHH: deoxyhypusine hydroxylase; Az: antizyme; AzI: antizyme inhibitor. http://dx.doi.org/10.4062/biomolther.2012.097 2 Park and Igarashi. Polyamine Metabolites as Markers of Cancer and Stroke Generation of acrolein and protein-conjugated acrolein by polyamine oxidase reactions. Acrolein generated by SMO, AcPAO or Fig. 2. BSAO reacts with e-amino group of lysine residues of proteins to form FDP-lysine containing adducts. BSAO: bovine serum amine oxidase; FDP-Lys: N-(3-formyl-3,4-dehydropiperidino)lysine. Polyamine oxidase (SMO or AcPAO) mediated reactions zymes, ODC, SAMDC and SSAT1 are highly regulated by cause oxidative stress to cells and tissues. In addition to a polyamines and by various stimuli such as growth factors, lower polyamine, SMO generates H O and 3-aminopropa- hormones, 12-O-tetradecanoylphorbol-1 3-acetate (TPA), etc 2 2 nal and AcPAO generates H O and 3-acetylaminopropanal (Pegg, 2009). In the presence of high levels of spermidine and 2 2 (Fig. 2). These aldehydes are unstable and spontaneously spermine in cells or medium, ODC and SAMDC are down- decompose to acrolein after deamination. Acrolein can be regulated while SSAT1 is upregulated. Reciprocally, when also generated extracellularly from spermine or spermidine in cellular polyamine levels are reduced, ODC and SAMDC are cell culture medium containing bovine serum amine oxidase upregulated and SSAT1 is downregulated. The regulation (BSAO) -like activity that oxidizes at the terminal amino group occurs at the transcriptional, translational, and posttransla- of polyamines (Sharmin et al., 2001). Acrolein, an unsaturated tional levels and specific mechanisms of regulation of these reactive aldehyde, is highly toxic and readily reacts with lysine enzymes by polyamines have been extensively investigated residues of proteins to form N -(3-formyl-3,4-dehydropiperidi- (Pegg, 2009; Igarashi and Kashiwagi, 2010). When the cel- no)lysine (FDP-lysine) (Uchida et al., 1998). lular polyamine level increases, ODC is downregulated by in- In addition to the polyamine interconversion pathway, a duction of antizyme (Az) translation by frame shifting (Ivanov small amount of cellular spermidine is covalently incorporat- et al., 1998; Coffino, 2001). The antizyme forms a complex ed into a specific cellular protein eIF5A to form an unusual with the ODC monomer to inactivate the enzyme and directs it amino acid hypusine [N -(4-amino-2-hydroxybutyl)lysine] to degradation by the 26S proteasome. In addition, antizyme (Fig.1) (Park, 2006; Park et al., 2010). The first step enzyme, inhibits polyamine uptake and stimulates its secretion. Further deoxyhypusine synthase (DHS) (Joe et al., 1995) catalyzes complexity of ODC regulation is introduced by an antizyme in- the NAD-dependent cleavage of spermidine between N4 hibitor (AzI) (Fujita et al., 1982), which shares high sequence and C5 and the transfer of aminobutyl moiety of spermidine similarity to ODC, but is devoid of the enzyme activity. to the e-amino-group of a specific lysine residue of the eIF5A precursor, eIF5A(Lys), to form a deoxyhypusine-containing intermediate, eIF5A(Dhp). This intermediate is subsequently PROPOSED FUNCTIONS OF POLYAMINES hydroxylated by deoxyhypusine hydroxylase (DOHH) (Park et al., 2006) to form hypusine and the biologically active, mature From gene disruption studies in yeast and mice (Jänne et eIF5A, eIF5A(Hpu). al., 2004), it is well established that polyamines are essen- The polyamine biosynthetic enzymes and catabolic en- tial for eukaryotic cell growth and mammalian development www.biomolther.org 3 Biomol Ther 21(1), 1-9 (2013) (Pegg, 2009). As mentioned above (Fig. 1), one well defined response element in the promoter region (for SSAT1) (Wang function of polyamine is the requirement for spermidine for hy- et al., 1998). pusine modification in eIF5A (Park, 2006; Park et al., 2010). In addition, polyamines have been proposed to play several Since eIF5A and its deoxyhypusine/hypusine modification are other important roles in cellular regulation and animal physiol- essential for eukaryotic cell growth and mouse development ogy (Pegg, 2009; Minois et al., 2011). Due to their interaction (Nishimura et al., 2012), the eIF5A modification defines one with DNA structure (Thomas and Thomas, 2001), their effects specific function of polyamines. Due to a narrow specificity on chromatin condensation (Matthews, 1993) and enzymes of DHS for spermidine, only natural polyamine or an analog such as HAT and HDAC (Hobbs et al., 2002) and protein ki- with closely related structure to spermidine can support long- nases/phosphatases (Lawson et al., 2005), polyamines may term growth of mammalian cells (Byers et al., 1994; Hyvönen also regulate transcription and gene expression, directly or et al., 2007). In addition to eIF5A modification, polycationic indirectly. The two oncogenes, c-Myc and c-Jun were reported polyamines are also essential for proliferation of mammalian to be transcriptionally controlled by polyamines in cells treated cells (Nishimura et al., 2005). These organic polycations fulfill with DFMO (Patel and Wang, 1997). The polyamine effects unique cellular functions that cannot be substituted by inor- on global transcription have been investigated by microarray 2+ ganic cations, such as Mg in macromolecular synthesis or in analyses in mammalian cells partially depleted of polyamine cell growth (Oredsson et al., 1984). Numerous studies have by treatment with DFMO (Landau et al., 2012). been reported on the effects of polyamines on DNA structure Polyamines also bind and regulate glutamate receptor ion (Thomas and Thomas, 2001), chromatin condensation (Mat- channels (Dingledine et al., 1999), inwardly rectifying potas- thews, 1993), RNA structure (Igarashi and Kashiwagi, 2010) sium channels (Kir) (Stanfield and Sutcliffe, 2003), and oth - and protein synthesis in vitro (Ogasawara et al., 1989). How- er channels that affect intracellular calcium signaling or Na ever, the molecular mechanism of polycationic polyamine ac- transport (Fleidervish et al., 2008). Although spermine is not tions in vivo has remained obscure for decades. required for mammalian cell growth, spermine synthase de- Insights on the cellular function of polyamines in protein fective mice (Gy mice) are totally deaf (Wang et al., 2009), synthesis have been offered by their cellular distribution, es- suggesting the importance of homeostasis of spermidine and timated from the individual dissociation constant for each of spermine in animal development and physiology. polyamine-partner binding under the physiological concentra- + 2+ tions of K and Mg of E. coli and mammalian cells (Igarashi and Kashiwagi, 2010). In mammalian cells and tissues, a ma- POLYAMINES, AGING AND HUMAN DISEASES jority of cellular spermidine and spermine (57-85%) appear to be bound to RNA, whereas free polyamines and the fractions Since polyamines are essential for cell growth and viability bound to other components (DNA, ATP or phospholipids) are (Pendeville et al., 2001; Nishimura et al., 2002), polyamine relatively small. Furthermore, the crystal structure of yeast levels change with aging, and under several disease condi- Phe tRNA revealed two molecules of spermine (Quigley et al., tions (Minois et al., 2011). Decrease in polyamines with aging 1978), suggesting specific interactions between polyamines was evaluated with mouse (Nishimura et al., 2006), and the and RNA. In in vitro translation assays, polyamines not only decrease in polyamine content was observed in almost all tis- 2+ lowered the Mg requirement, but also stimulated protein sues, and it was especially notable in skin, heart and muscle. 2+ synthesis beyond the maximum level achieved by high Mg The decrease was not significant in brain and pancreas. It also alone (Ogasawara et al., 1989). In addition, polyamines were became clear that polyamine-rich food decreases mortality in reported to exert several other effects on translation, including aged mice (Soda et al., 2009). stimulation of the assembly of the 30S ribosome, rat liver Ile- Deregulation of the polyamine pathway enzymes has been tRNA formation, an increase in the fidelity of protein synthesis implicated in various pathological conditions, including cancer and frame shifting (Igarashi and Kashiwagi, 2010). (Gerner and Meyskens, 2004; Casero and Marton, 2007), in- More recently, further evidence for a primary function of flammation (Babbar et al., 2007), stroke (Tomitori et al., 2005; polyamines in translation was obtained in mammalian cells Yoshida et al., 2010; Igarashi and Kashiwagi, 2011b; Saiki et over-expressing SSAT1. Rapid arrest in protein synthesis and al., 2011), renal failure (Igarashi et al., 2006) and diabetes cell growth occurred in these cells depleted of spermidine and (Kramer et al., 2008). spermine by SSAT1 over-expression, whereas there was little As for cancer, Russell and Snyder first reported high levels or no inhibition of synthesis of DNA and RNA (Mandal et al., of ODC activity in regenerating rat liver and in several human 2013). These findings are consistent with specific interactions cancers (Russell and Snyder, 1968). Since then, effects of in- of polyamines with RNA (Igarashi and Kashiwagi, 2010), and hibitors of polyamine biosynthesis; i.e., a-difluoromethylorni - their stimulatory effects on protein synthesis in vitro (Ogas- thine (DFMO) (Mamont et al., 1978), an inhibitor of ODC, and awara et al., 1989), and corroborate an important function of methylglyoxal bis(guanylhaydrazone) (MGBG) (Williams-Ash- the polyamines spermidine and spermine in translation. Thus, man and Schenone, 1972), an inhibitor of SAMDC, on cancer polyamines appear to contribute to mammalian cell growth growth were extensively studied with mice bearing various mainly through their participation in eIF5A hypusine modifica - cancers. The combination of DFMO-MGBG has been shown tion (Park, 2006) and by stimulating translation initiation by to be more effective therapeutically than either drug alone in enhancing ribosome assembly and stability (Ogasawara et a number of in vivo model systems, which include Ehrlich as- al., 1989). Specific genes influenced by cellular polyamines at cites carcinoma (Seppänen et al., 1983), murine L1210 and translation include Az, SAMDC, and SSAT1 and their regula- P388 leukemia (Kramer et al., 1985; Nakaike et al., 1988), tion involves different mechanisms, including ribosome frame and murine renal adenocarcinoma (Herr et al., 1984). Further- shifting (for Az) (Ivanov et al., 1998), a small upstream open more, the stronger antitumor effects were exerted when mice reading frame (for SAMDC) (Mize et al., 1998), and polyamine were fed a polyamine-deficient diet (Nakaike et al., 1988), http://dx.doi.org/10.4062/biomolther.2012.097 4 Biomol Ther 21(1), 1-9 (2013) al., 2007), and second, an unsaturated aldehyde such as ac- rolein (Stevens and Maier, 2008). Addition of SPD and SPM to culture medium containing ruminant serum causes inhibi- tion of cell proliferation (Higgins et al., 1969; Agostinelli et al., 2010). This effect is caused by oxidation products of the poly- amines by ruminant amine oxidase, H O and acrolein (Fig. 2 2 2). In a cell culture system, complete inhibition of cell growth was accomplished with 10 mM acrolein, 100 mM H O and 20 2 2 mM hydroxylradical produced by 20 mM H O and 1 mM Vita- 2 2 min C (Yoshida et al., 2009), suggesting acrolein as the major toxic agent. These findings led us to test whether acrolein or protein-conjugated acrolein (PC-Acro) is a good biochemical marker for stroke and chronic renal failure. At present, there is no reliable biochemical marker for diag- nosis of the early stage of stroke. Thus, the activities of sperm- ine oxidase (SMO) and acetylpolyamine oxidase (AcPAO) were measured along with the level of PC-Acro in plasma of patients with stroke (Tomitori et al., 2005). PC-Acro was metowardasured by ELISA using anti-FDP-lysine antibody (Uchida et al., 1998). The median levels of PC-Acro and to- tal polyamine oxidases (SMO and AcPAO) were significantly higher in the plasma of patients with stroke. The median lev- els of PC-Acro and total polyamine oxidase activity (PAO) in plasma increased from 14.4 to 21.3 nmol/ml plasma and from 4.5 to 8.0 nmol SPD produced from SPM by PAO/ml plasma, respectively. It was then examined whether the increases in PC-Acro and PAO are correlated with the severity of stroke (size of the infarct). Because the maximal increase in PAO precedes that in PC-Acro, the multiplied value of PAO by PC- Acro was compared with the size of the infarct. Statistical significance between stroke patients and no-stroke subjects −7 became greater in the multiplied value (p=9.3×10 ) than PAO −5 −6 (p=7.0×10 ) or PC-Acro (p=6.6×10 ). The size of the infarct was nearly parallel with the value of PAO activity multiplied by PC-Acro amount (Tomitori et al., 2005). Correlation between brain infarction and PC-Acro in PIT Fig. 3. There are reports that silent brain infarction (SBI) increases model mice. (A) Infarction volume at 24 h after the induction of infarction, the level of PC-Acro estimated by Western blotting us- the risk of subsequent stroke (Vermeer et al., 2007), dementia ing anti-FDP-Lys antibody, and polyamine levels at the locus of (Vermeer et al., 2007), and mild cognitive impairment (Lopez brain infarction and at the corresponding locus in normal mice et al., 2003). Furthermore, it has been reported that carotid are shown. (B) Increase in PC-Acro and polyamines in plasma of atherosclerosis (CA) is a risk factor for stroke and SBI (In- PIT model mice with brain infarction is shown. *p<0.05, **p<0.01, oue et al., 2007), and that SBI and white matter hyperintensity ***p<0.001. Data were adapted from Saiki et al. (2009). (WMH) increase the risk for stroke and mortality (Bokura et al., 2006). Thus, it was tested how PC-Acro is correlated with SBI, WMH and CA by collecting blood from 790 elderly healthy volunteers. Since the levels of CRP and IL-6 are reported to lyzed together with age as a factor. The median RRV (relative increase in the serum of apparently healthy individuals with risk value) for SBI with CA (93 subjects), SBI (214 subjects), SBI (Hoshi et al., 2005), the levels of CRP and IL-6 were mea- CA (263 subjects), WMH with CA (90 subjects), WMH (245 sured along with PC-Acro (Yoshida et al., 2010). SBI (affected subjects) and control (260 subjects) was 0.90, 0.80, 0.76, areas ≥3 mm diameter) and WMH were estimated by MRI, 0.65, 0.46 and 0.14, respectively. Although PC-Acro is well CA by carotid ultrasound examination, and CRP and IL-6 in correlated with brain infarction, measurement of IL-6 and CRP plasma by ELISA. PC-Acro, IL-6 and CRP were significantly along with PC-Acro was necessary to increase sensitivity and higher in SBI and CA compared with the control. PC-Acro was specificity to detect SBI. most strongly correlated with CA, and IL-6 and CRP with SBI The role of PC-Acro and polyamine oxidases was also (Yoshida et al., 2010). Thus, CA is likely the primary risk factor evaluated in an animal model of stroke by using photochemi- related to stroke in this analysis. cally induced thrombosis (PIT) model mice (Fig. 3) (Saiki et It was next determined whether SBI, CA and WMH could be al., 2009). In this model, it was determined whether acrolein detected by altered levels of PC-Acro, IL-6 and CRP using a is produced from polyamines at the locus of infarction. The receiver operating characteristic (ROC) curve – a commonly volume of infarcted tissue was determined by staining 2-mm- used technique for assessing diagnostic and predictive accu- thick coronal slices with triphenyltetrazolium, which stains the racy in disease management (Linden, 2006). Since age was viable brain tissue red whereas infarcted tissue remains un- an important factor among various markers evaluated for the stained. The average volume of infarction at 24 h of PIT model detection of SBI, CA and WMH, these three values were ana- mice was 23 mm (Fig. 3A). The PC-Acro determined by west- http://dx.doi.org/10.4062/biomolther.2012.097 6 Biomol Ther 21(1), 1-9 (2013) duplication and keratosis follicularis spinulosa decalvans (KFSD). Biochem. 139, 315-322. Hum. Genet. 111, 235-241. Kramer, D. L., Diegelman, P., Jell, J., Vujcic, S., Merali, S. and Porter, Giorgio, M., Trinei, M., Migliaccio, E. and Pelicci, P. G. (2007) Hydro- C. W. (2008) Polyamine acetylation modulates polyamine meta- gen peroxide: a metabolic by-product or a common mediator of bolic flux, a prelude to broader metabolic consequences. J. Biol. ageing signals? Nat. Rev. Mol. Cell Biol. 8, 722-728. Chem. 283, 4241-4251. Gomez, M. and Hellstrand, P. (1995) Effects of polyamines on voltage- Kramer, D. L., Paul, B. and Porter, C. W. (1985) Effect of pretreatment activated calcium channels in guinea-pig intestinal smooth muscle. with alpha-difluoromethylornithine on the selectivity of methylglyox - Pflugers Arch. 430, 501-507. al bis(guanylhydrazone) for tumor tissue in L1210 leukemic mice. Herr, H. W., Kleinert, E. L., Conti, P. S., Burchenal, J. H. and Whitmore, Cancer Res. 45, 2512-2515. W.F., Jr. (1984) Effects of alpha-difluoromethylornithine and meth - Landau, G., Ran, A., Bercovich, Z., Feldmesser, E., Horn-Saban, S., ylglyoxal bis(guanylhydrazone) on the growth of experimental renal Korkotian, E., Jacob-Hirsh, J., Rechavi, G., Ron, D. and Kahana, adenocarcinoma in mice. Cancer Res. 44, 4382-4385. C. (2012) Expression profiling and biochemical analysis suggest Higgins, M. L., Tillman, M. C., Rupp, J. P. and Leach, F. R. (1969) stress response as a potential mechanism inhibiting proliferation of The effect of polyamines on cell culture cells. J. Cell. Physiol. 74, polyamine-depleted cells. J. Biol. Chem. 287, 35825-35837. 149-154. Lawson, K., Larentowicz, L., Laury-Kleintop, L. and Gilmour, S. K. Hiramatsu, K., Takahashi, K., Yamaguchi, T., Matsumoto, H., Miyamo- (2005) B23 is a downstream target of polyamine-modulated CK2. to, H., Tanaka, S., Tanaka, C., Tamamori, Y., Imajo, M., Kawaguchi, Mol. Cell. Biochem. 274, 103-114. 1 12 M. et al. (2005) N( ),N( )-Diacetylspermine as a sensitive and spe- Linden, A. (2006) Measuring diagnostic and predictive accuracy in dis- cific novel marker for early- and late-stage colorectal and breast ease management: an introduction to receiver operating character- cancers. Clin. Cancer Res. 11, 2986-2990. istic (ROC) analysis. J. Eval. Clin. Pract. 12, 132-139. Hobbs, C. A., Paul, B. A. and Gilmour, S. K. (2002) Deregulation of Lopez, O. L., Jagust, W. J., Dulberg, C., Becker, J. T., DeKosky, S. T., polyamine biosynthesis alters intrinsic histone acetyltransferase Fitzpatrick, A., Breitner, J., Lyketsos, C., Jones, B., Kawas, C. et and deacetylase activities in murine skin and tumors. Cancer Res. al. (2003) Risk factors for mild cognitive impairment in the Cardio- 62, 67-74. vascular Health Study Cognition Study: part 2. Arch. Neurol. 60, Hoshi, T., Kitagawa, K., Yamagami, H., Furukado, S., Hougaku, H. and 1394-1399. Hori, M. (2005) Relations of serum high-sensitivity C-reactive pro- Mamont, P. S., Duchesne, M. C., Grove, J. and Bey, P. (1978) Anti- tein and interleukin-6 levels with silent brain infarction. Stroke 36, proliferative properties of DL-alpha-difluoromethyl ornithine in cul - 768-772. tured cells. A consequence of the irreversible inhibition of ornithine Hyvönen, M. T., Keinanen, T. A., Cerrada-Gimenez, M., Sinervirta, R., decarboxylase. Biochem. Biophys. Res. Commun. 81, 58-66. Grigorenko, N., Khomutov, A. R., Vepsalainen, J., Alhonen, L. and Mandal, S., Mandal, A., Johansson, H. E., Orjalo, A. V. and Park, M. H. Janne, J. (2007) Role of hypusinated eukaryotic translation initia- (2013) Depletion of cellular polyamines, spermidine and spermine, tion factor 5A in polyamine depletion-induced cytostasis. J. Biol. causes a total arrest in translation and growth in mammalian cells. Chem. 282, 34700-34706. Proc. Natl. Acad. Sci. USA in press published ahead of print Janu- Igarashi, K. and Kashiwagi, K. (2000) Polyamines: mysterious modula- ary 23, 2013, doi:10.1073/pnas.1219002110 tors of cellular functions. Biochem. Biophys. Res. Commun. 271, Matthews, H. R. (1993) Polyamines, chromatin structure and transcrip- 559-564. tion. Bioessays 15, 561-566. Igarashi, K. and Kashiwagi, K. (2010) Modulation of cellular function by Minois, N., Carmona-Gutierrez, D. and Madeo, F. (2011) Polyamines polyamines. Int. J. Biochem. Cell Biol. 42, 39-51. in aging and disease. Aging (Albany NY) 3, 716-732. Igarashi, K. and Kashiwagi, K. (2011a) Use of polyamine metabolites Mize, G. J., Ruan, H., Low, J. J. and Morris, D. R. (1998) The inhibitory as markers for stroke and renal failure. Methods Mol. Biol. 720, upstream open reading frame from mammalian S-adenosylmethio- 395-408. nine decarboxylase mRNA has a strict sequence specificity in criti - Igarashi, K. and Kashiwagi, K. (2011b) Protein-conjugated acrolein as cal positions. J. Biol. Chem. 273, 32500-32505. a biochemical marker of brain infarction. Mol. Nutr. Food Res. 55, Nakaike, S., Kashiwagi, K., Terao, K., Iio, K. and Igarashi, K. (1988) 1332-1341. Combined use of alpha-difluoromethylornithine and an inhibitor of Igarashi, K., Ueda, S., Yoshida, K. and Kashiwagi, K. (2006) Poly- S-adenosylmethionine decarboxylase in mice bearing P388 leuke- amines in renal failure. Amino Acids 31, 477-483. mia or Lewis lung carcinoma. Jpn. J. Cancer Res. 79, 501-508. Inoue, K., Matsumoto, M., Shono, T., Toyokawa, S. and Moriki, A. Nishimura, K., Lee, S. B., Park, J. H. and Park, M. H. (2012) Essential (2007) Increased intima media thickness and atherosclerotic role of eIF5A-1 and deoxyhypusine synthase in mouse embryonic plaques in the carotid artery as risk factors for silent brain infarcts. development. Amino Acids 42, 703-710. J. Stroke Cerebrovasc. Dis. 16, 14-20. Nishimura, K., Murozumi, K., Shirahata, A., Park, M. H., Kashiwagi, K. Ivanov, I. P., Gesteland, R. F., Matsufuji, S. and Atkins, J. F. (1998) Pro- and Igarashi, K. (2005) Independent roles of eIF5A and polyamines grammed frameshifting in the synthesis of mammalian antizyme is in cell proliferation. Biochem. J. 385, 779-785. +1 in mammals, predominantly +1 in fission yeast, but -2 in bud - Nishimura, K., Nakatsu, F., Kashiwagi, K., Ohno, H., Saito, T. and Iga- ding yeast. RNA 4, 1230-1238. rashi, K. (2002) Essential role of S-adenosylmethionine decarbox- Jänne, J., Alhonen, L., Pietila, M. and Keinanen, T. A. (2004) Genetic ylase in mouse embryonic development. Genes Cells 7, 41-47. approaches to the cellular functions of polyamines in mammals. Nishimura, K., Shiina, R., Kashiwagi, K. and Igarashi, K. (2006) De- Eur. J. Biochem. 271, 877-894. crease in polyamines with aging and their ingestion from food and Jin, L., Miyazaki, M., Mizuno, S., Takigawa, M., Hirose, T., Nishimura, drink. J. Biochem. 139, 81-90. K., Toida, T., Williams, K., Kashiwagi, K. and Igarashi, K. (2008) Ogasawara, T., Ito, K. and Igarashi, K. (1989) Effect of polyamines The pore region of N-methyl-D-aspartate receptors differentially on globin synthesis in a rabbit reticulocyte polyamine-free protein influences stimulation and block by spermine. J. Pharmacol. Exp. synthetic system. J. Biochem. 105, 164-167. Ther. 327, 68-77. Oredsson, S. M., Alm, K., Dahlberg, E., Holst, C. M., Johansson, V. M., Joe, Y. A., Wolff, E. C. and Park, M. H. (1995) Cloning and expres- Myhre, L. and Soderstjerna, E. (2007) Inhibition of cell proliferation sion of human deoxyhypusine synthase cDNA. Structure-function and induction of apoptosis by N1,N11-diethylnorspermine-induced studies with the recombinant enzyme and mutant proteins. J. Biol. polyamine pool reduction. Biochem. Soc. Trans. 35, 405-409. Chem. 270, 22386-22392. Oredsson, S. M., Anehus, S. and Heby, O. (1984) Reversal of the Kaasinen, S. K., Oksman, M., Alhonen, L., Tanila, H. and Janne, J. growth inhibitory effect of alpha-difluoromethylornithine by putres - (2004) Spermidine/spermine N1-acetyltransferase overexpression cine but not by other divalent cations. Mol. Cell. Biochem. 64, 163- in mice induces hypoactivity and spatial learning impairment. Phar- 172. macol. Biochem. Behav. 78, 35-45. Park, J. H., Aravind, L., Wolff, E. C., Kaevel, J., Kim, Y. S. and Park, M. Kawakita, M. and Hiramatsu, K. (2006) Diacetylated derivatives of H. (2006) Molecular cloning, expression, and structural prediction spermine and spermidine as novel promising tumor markers. J. of deoxyhypusine hydroxylase: a HEAT-repeat-containing metallo- http://dx.doi.org/10.4062/biomolther.2012.097

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