Differential expression of IL-6/IL-6R and MAO-A regulates
invasion/angiogenesis in breast cancer
, Goutam Dey
, Anjan Kumar Das
and Mahitosh Mandal
BACKGROUND: Monoamine oxidases (MAO) are mitochondrial enzymes functioning in oxidative metabolism of monoamines. The
action of MAO-A has been typically described in neuro-pharmacological domains. Here, we have established a co-relation between
IL-6/IL-6R and MAO-A and their regulation in hypoxia induced invasion/angiogenesis.
METHODS: We employed various in-vitro and in-vivo techniques and clinical samples.
RESULTS: We studied a co-relation among MAO-A and IL-6/IL-6R and tumour angiogenesis/invasion in hypoxic environment in
breast cancer model. Activation of IL-6/IL-6R and its downstream was found in hypoxic cancer cells. This elevation of IL-6/IL-6R
caused sustained inhibition of MAO-A in hypoxic environment. Inhibition of IL-6R signalling or IL-6R siRNA increased MAO-A activity
and inhibited tumour angiogenesis and invasion signiﬁcantly in different models. Further, elevation of MAO-A with 5-azacytidine
(5-Aza) modulated IL-6 mediated angiogenesis and invasive signatures including VEGF, MMPs and EMT in hypoxic breast
cancer. High grade invasive ductal carcinoma (IDC) clinical specimen displayed elevated level of IL-6R and depleted MAO-A
expression. Expression of VEGF and HIF-1α was unregulated and loss of E-Cadherin was observed in high grade IDC tissue
CONCLUSIONS: Suppression of MAO-A by IL-6/IL-6R activation promotes tumour angiogenesis and invasion in hypoxic breast
British Journal of Cancer (2018) 118:1442–1452; https://doi.org/10.1038/s41416-018-0078-x
Breast cancer is a deadly disease affecting the women health
worldwide. Despite the advanced research since previous
decades, it is further required to explore the molecular
landscape of cancer progression, angiogenesis and metastasis.
A number of functional activities of regulatory proteins have
been discovered in cancer associated patho-biological states
including tumour angiogenesis/invasion. Monoamine oxidase A
(MAO-A) is an enzyme encoded by MAO-A gene. MAO-A is
responsible for degradation and catalyzation of endogenous
neurotransmitters amines including phenylethylamine, tyra-
mine, serotonin, norepinephrine and dopamine in central, as
well as peripheral region of the body.
Critical roles of MAO-A
have been discovered in context to a number of neurological
disorders. MAO-A and another form MAO-B are generally
present in outer mitochondrial membrane.
However, there is
a lack of knowledge in the domain of MAO-A involvement in
cancer progression, metastasis and angiogenesis. Previous
report showed that, MAO-A level was signiﬁcantly decreased
in multiple cancer types including breast cancer
adjacent normal tissues. In another investigation, serum starved
apoptosis was co-related with increased MAO-A, caspase and
MAPK expression in human neuroblastoma cells.
MAO-A plays a
critical role in staurosporine induced apoptotic cell death via
altering caspase, Bcl-2 and p38/MAPK in SH-SY5Y human
Clorgyline which is a MAO-A inhibitor
can suppress the apoptotic effect of serum starvation in
Overall, MAO-A expression is reduced in
Interleukin-6 (IL-6) is a cytokine mainly involved in a number
of inﬂammatory conditions.
Growing evidences suggested
that this cytokine was also involved in cancer progression,
metastasis, chemo-resistance, angiogenesis and epithelial to
IL-6 is associated with more aggres-
sive and invasive phenotype of cancer. IL-6 acts as a growth
factor and fuels cancer progression through activating a series
of downstream signalling cascade including gp130, JAK/STAT,
MAPK, and Akt.
In this study, we found that decreased level of MAO-A promotes
tumour angiogenesis and invasion in breast cancer model in
hypoxic environment. The activity of MAO-A is found to be
negatively regulated by IL-6/IL-6R. Increased MAO-A was found to
cause inhibition of angiogenic and invasive features of breast
cancer cells. Inhibition of IL-6/IL-6R signalling by Diacerein (Dia)
can suppress angiogenesis/invasion by up-regulating MAO-A
expression. This study presents role of IL-6/IL-6R-MAO-A signalling
axis in invasion/angiogenesis in hypoxic tumour environment and
highlights this signalling as critical target for cancer therapy.
Received: 12 November 2017 Revised: 27 February 2018 Accepted: 14 March 2018
Published online: 26 April 2018
School of Medical Science and Technology, Indian Institute of Technology Kharagpur, Kharagpur 721302, India and
Department of Pathology, Calcutta National Medical
Collage, Kolkata, West Bengal 70014, India
Correspondence: Mahitosh Mandal (firstname.lastname@example.org)
These authors contributed equally: Rashmi Bharti, Goutam Dey.
© Cancer Research UK 2018