Purpose: TNF-related apoptosis-inducing ligand (TRAIL) resistance significantly limits its use in clinical practice. It has been reported that 2-deoxy-D-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 apoptosis.
Conclusions: Taken together, we show that 2-DG can sensitize TRAIL-induced apoptosis, at least in part, through suppressing 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: 2-DG; Apoptosis; Autophagy; Gastric cancer; JNK; TRAIL.