Inhibition of active autophagy induces apoptosis and increases chemosensitivity in cholangiocarcinoma

Intrahepatic cholangiocellular carcinomas (ICCs) are usually fatal neoplasms originating from bile duct epithelia. However, many cholangiocarcinoma cells are shown to be resistant to chemotherapeutic drugs, which induce cell apoptosis. The role of autophagy and the therapeutic value of autophagy-associated genes are largely unknown in ICC. Here, we showed that autophagy was activated in nutrient starvation and xenograft cholangiocarcinoma cells. Furthermore, expression of autophagic genes and their autophagic activity were higher in clinical ICC specimens than that in normal cholangiocytes separated by laser capture microdissection. Inhibition of autophagy by autophagy inhibitors or siRNA, cholangiocarcinoma cells showed detention of proliferation and increase of apoptosis during nutrient starvation. In addition, autophagy inhibitor treatment or knockdown of beclin 1 suppressed tumor growth and sensitized ICC cells to chemotherapeutic agent-induced cell death. In conclusion, our data showed that autophagy is activated in ICC, and inactivation of autophagy may lead to cell apoptosis and enhance chemotherapy sensitivity. Laboratory Investigation (2011) 91, 1146-1157; doi:10.1038/labinvest.2011.97; published online 6 June 2011