Autophagy in pancreatic cancer pathogenesis and treatment

Pancreatic cancer is the fourth most common cancer to cause death due to advanced stage at diagnosis and poor response to current treatment. Autophagy is the lysosome-mediated degradation pathway which plays a critical role in cellular defense, quality control, and energy metabolism. Targeting autophagy is now an exciting field for translational cancer research, as autophagy dysfunction is among the hallmarks of cancer. Pancreatic tumors have elevated autophagy under basal conditions when compared with other epithelial cancers. This review describes our current understanding of the interaction between autophagy and pancreatic cancer development, including risk factors (e.g., pancreatitis, smoking, and alcohol use), tumor microenvironment (e.g., hypoxia and stromal cells), and molecular biology (e.g., K-Ras and p53) of pancreatic cancer. The importance of the HMGB1-RAGE pathway in regulation of autophagy and pancreatic cancer is also presented. Finally, we describe current studies involving autophagy inhibition using either pharmacological inhibitors (e.g., chloroquine) or RNA interference of essential autophagy genes that regulate chemotherapy sensitivity in pancreatic cancer. Summarily, autophagy plays multiple roles in the regulation of pancreatic cancer pathogenesis and treatment, although the exact mechanisms remain unknown.