Inhibition of autophagy by Atg7 knockdown enhances chemosensitivity in gemcitabine/paclitaxel-resistant pancreatic cancer MIAPaCa2 cells.

Abstract

The 5-year survival rate for pancreatic cancer is extremely low, at approximately 12%, primarily because most patients present with advanced and unresectable tumors. Chemotherapy regimens, such as gemcitabine (GEM) plus paclitaxel (PTX) and FOLFIRINOX, are standard treatments; however, resistance to these therapies remains a major challenge. Autophagy has been implicated in this resistance. Both the Atg8 and Atg12 conjugation systems are essential for autophagosome maturation, and the ubiquitin-like protein activator Atg7 plays an essential role in these systems. This study investigated the effects of Atg7 knockdown on GEM/PTX sensitivity in GEM/PTX-resistant pancreatic cancer MIAPaCa2 (GP-R) cells. GP-R cells exhibited reduced sensitivity to GEM/PTX, increased expression of autophagy-related factors, and elevated basal autophagy compared to parental cells. Atg7 knockdown in GP-R cells effectively inhibited both basal and GEM/PTX-induced autophagy, significantly increased total and mitochondrial reactive oxygen species (ROS), and led to the induction of apoptotic cell death. These findings suggest that autophagy inhibition via Atg7 knockdown enhances GEM/PTX sensitivity in GP-R cells. In conclusion, targeting Atg7 to inhibit autophagy may be a promising approach to improving the efficacy of GEM/PTX therapy in pancreatic cancer.