Cancer Chemotherapy and Pharmacology (2018) 81:555–564
-glucose enhances TRAIL-induced apoptosis in human
gastric cancer cells through downregulating JNK-mediated
· Qingling Wang
· Lin Zhang
· Maojin Zheng
Received: 16 October 2017 / Accepted: 20 January 2018 / Published online: 31 January 2018
© Springer-Verlag GmbH Germany, part of Springer Nature 2018
Purpose TNF-related apoptosis-inducing ligand (TRAIL) resistance signiﬁcantly limits its use in clinical practice. It has
been reported that 2-deoxy-
-glucose (2-DG) can enhance TRAIL’s cytotoxicity. Our studies were designed to investigate
the mechanisms of 2-DG reversing TRAIL resistance therapy in gastric cancer cells.
Methods Gastric cancer cells (MGC803, SGC7901) were treated with 2-DG and TRAIL. Cell viability was determined by
CCK-8 assay and detection of apoptosis by ﬂow cytometry. Autophagic and apoptosis protein expression and c-Jun NH2-
terminal kinase (JNK) phosphorylation were determined by Western blotting. Autophagy response and JNK activities were
inhibited by speciﬁc inhibitor, 3MA or SP600125, respectively. LDH release assay was used to detect cytotoxicity.
Results We conﬁrmed that TRAIL triggered an autophagic response in TRAIL-resistant gastric cancer cells, MGC803
and SGC7901, and depended on JNK activation. Blocking autophagy or JNK activation with speciﬁc inhibitor, 3MA or
SP600125, potentiated cell death and caspase-3 activation. Furthermore, we conﬁrmed that 2-DG inhibited the viability
of gastric cancer cells, phosphorylation of JNK induced by TRAIL and increased gastric cancer cells to TRAIL-induced
Conclusions Taken together, we show that 2-DG can sensitize TRAIL-induced apoptosis, at least in part, through suppress-
ing JNK-mediated cytoprotective autophagic signaling in MGC803 and SGC7901cells. These results may have signiﬁcant
implications for the development of new strategies to reverse TRAIL resistance in gastric tumor.
Keywords Gastric cancer · TRAIL · 2-DG · JNK · Autophagy · Apoptosis
An estimated 951,600 new gastric cancer cases and 723,100
deaths occurred in 2012 . Thus, eﬃcient strategies were
highly required for gastric cancer treatment. TNF-related
apoptosis-inducing ligand (TRAIL) is a promising anti-
cancer agent because it selectively induces apoptosis in
cancer cells but spares normal cells. TRAIL induces cell
death through binding to its death receptors TRAIL-R1
(also referred to as DR4) and TRAIL-R2 (DR5) on the cell
membrane . After activating caspase-8, it would activate
the cell apoptosis directly or indirectly by the mitochondrial
apoptotic response . Recombinant TRAIL and monoclo-
nal antibody against TRAIL-Rs are currently in clinical
evaluation for the treatment of all kinds of cancers . How-
ever, in a variety of tumor types, including gastric tumor,
resistance of cancer cells to TRAIL-mediated cell apoptosis
remains a major obstacle for TRAIL-based cancer therapy;
therefore, combination therapies are under investigation .
2-DG is a synthetic analogue of glucose diﬀering at the
second carbon. After entering the cells through the glucose
transporter, it was phosphorylated by hexokinase to 2-DG-
phosphate, resulting in inhibition of glucose metabolism .
2-DG can also restrain protein glycosylation . It plays
an important role in the inhibition of cell growth, increases
chemotherapy drugs’ curative eﬀect and TRAIL-induced
apoptosis [8, 9].
Electronic supplementary material The online version of this
article (https ://doi.org/10.1007/s0028 0-018-3526-7) contains
supplementary material, which is available to authorized users.
* Yuting Xu
Department of Pathology, Xuzhou Medical University,
Xuzhou 221004, Jiangsu, China