Abstract 4107: Possible role of autophagy inhibition in hypoxia-induced chemoresistance of pancreatic cancer cells

Abstract

Abstract BACKGROUND: Autophagy is a catabolic process and provides metabolic support for the cell by degradation of intracellular macromolecules. Various types of stress, including hypoxia, activate autophagy. Recent studies have suggested that hypoxia has been shown to associate with resistance to chemotherapy and radiotherapy and hence poor prognosis in pancreatic cancer. This study investigated the role of autophagy in the treatment of pancreatic cancer with gemcitabine under hypoxic condition. METHODS: To evaluate the role of autophagy inhibition in hypoxia-induced chemoresistance, BxPC-3 human pancreatic cancer cell line was used under normoxic and hypoxic conditions. We evaluated the extent of LC3-II, as an autophagosome marker, by Western blotting to measure the hypoxia- or chemotherapy-induced autophagy. We then examined the effects of gemcitabine on induction of apoptosis under normoxic and hypoxic conditions. Finally, to determine the effect of 3-MA, a known inhibitor of autophagy, on overcoming hypoxia-induced chemoresistance, the MTS assay and flow cytometry were performed.RESULTS: Compared with normoxia, gemcitabine-induced cell death was significantly decreased under hypoxia, as a result of the reduced apoptosis. Western blotting analysis demonstrated that LC3-II was increased under hypoxia, compared with normoxia. However, we found that 3-MA can enhance the growth inhibition and apoptotic effect of gemcitabine, even under hypoxia. These findings mean that autophagy mediates the chemoresistance under hypoxia. Conclusions: Activated autophagy plays a role in hypoxia-induced chemoresistance of pancreatic cancer cells. These findings may have important implications for future therapeutic strategies using gemcitabine against pancreatic cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4107. doi:1538-7445.AM2012-4107