title: Inhibition of active autophagy induces apoptosis and increases chemosensitivity in cholangiocarcinoma.
abstract: 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.
authors.affiliation: International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, The Second Military Medical University, Shanghai, People's Republic of China.
authors.forename: Yu-Jie
authors.initials: YJ
authors.lastname: Hou
authors.forename: Li-Wei
authors.initials: LW
authors.lastname: Dong
authors.forename: Ye-Xiong
authors.initials: YX
authors.lastname: Tan
authors.forename: Guang-Zhen
authors.initials: GZ
authors.lastname: Yang
authors.forename: Yu-Fei
authors.initials: YF
authors.lastname: Pan
authors.forename: Zhong
authors.initials: Z
authors.lastname: Li
authors.forename: Liang
authors.initials: L
authors.lastname: Tang
authors.forename: Min
authors.initials: M
authors.lastname: Wang
authors.forename: Qing
authors.initials: Q
authors.lastname: Wang
authors.forename: Hong-Yang
authors.initials: HY
authors.lastname: Wang
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D001343:Autophagy / Q000187:drug effects*; D001650:Bile Duct Neoplasms / Q000188:drug therapy* / Q000473:pathology; D001653:Bile Ducts, Intrahepatic / Q000473:pathology*; D045744:Cell Line, Tumor; D018281:Cholangiocarcinoma / Q000188:drug therapy* / Q000473:pathology; D006801:Humans; D051379:Mice; D008819:Mice, Nude
chemical_list: D000970:Antineoplastic Agents