Mcl–1 Promotes Drug Resistance in Pancreatic Cancer Cells

Abstract

Due to the lack of effective therapy, pancreatic adenocarcinoma is unalteredly causing every fifth cancer–related death in the western world. On the cellular level, resistance to conventional chemotherapy is reflected by a pronounced apoptosis resistance of pancreatic cancer cells. In search of stimuli overcoming apoptosis resistance in pancreatic cancer, we found that UV-irradiation rapidly induced apoptosis in all of 11 pancreatic cancer cell lines (n=11) tested. UV-induced apoptosis occurred rapidly, was dose-dependent and did not require ongoing protein synthesis. Activation of Bax and release of cytochrom c occurred independently of caspase-activity. On the mitochondrial level, rapid elimination of Mcl–1 occurred upstream of Bax-activation. Blocking Mcl–1-degradation by inhibition of the proteasome, completely abolished UV-induced activation of Bax, activation of effector caspases and subsequent induction of cell death. However, elimination of Mcl–1 by siRNA-mediated knockdown was not sufficient to induce apoptosis, and knockdown of Mcl–1 did not affect tumor cell growth in vitro. In contrast, knockdown of Mcl–1 strongly sensitized pancreatic cancer cells to very low doses of UVC-irradiation. Most strinkingly, knockdown of Mcl–1 sensitized pancreatic cancer cells to various cytotoxic stimuli. These results point to a major role of Mcl–1 as an inhibitor of apoptosis in response to various stimuli in pancreatic cancer cells. Our findings suggest that elimination of Mcl–1 may extremely facilitate the induction of apoptosis in response to cytotoxic drugs. Thus, pharmacological targeting of Mcl–1 may be an attractive strategy to overcome drug resistance in pancreatic cancer.