title: Targeting autophagy potentiates chemotherapy-induced apoptosis and proliferation inhibition in hepatocarcinoma cells.
abstract: Induction of cell death and inhibition of cell growth are the main targets of cancer therapy. Here we evaluated the role of autophagy on chemoresistance of human hepatocarcinoma (HCC) cell lines, focusing on its crosstalk with cell apoptosis and proliferation. In this study, a chemotherapeutic agent (cisplatin or 5FU) induced the formation of autophagosomes in three human HCC cell lines and upregulated the expression of autophagy protein LC3-II. Inhibition of autophagy by 3-methyladenine or si-beclin 1 increased chemotherapy-induced apoptosis in HCC cells. Meanwhile, increased damage of the mitochondrial membrane potential was also observed in HCC cells when autophagy was inhibited. Furthermore, inhibition of autophagy reduced clone formation and impaired cell growth of HCC cells when treated with chemotherapy. Co-administration of an autophagy inhibitor (chloroquine) and chemotherapy significantly inhibited tumor growth in a mouse xenograft tumor model, with greater extent of apoptosis and impaired proliferation of tumor cells. This study suggests that autophagy is a potential novel target to improve therapy efficiency of conventional chemotherapeutics towards HCC.
authors.affiliation: Tumor Immunology and Gene Therapy Center, Eastern Hepatobiliary Surgery Hospital, The Second Military Medical University, Shanghai, PR China.
authors.forename: Xian-Ling
authors.initials: XL
authors.lastname: Guo
authors.forename: Ding
authors.initials: D
authors.lastname: Li
authors.forename: Fei
authors.initials: F
authors.lastname: Hu
authors.forename: Jian-Rui
authors.initials: JR
authors.lastname: Song
authors.forename: Shan-Shan
authors.initials: SS
authors.lastname: Zhang
authors.forename: Wei-Jie
authors.initials: WJ
authors.lastname: Deng
authors.forename: Kai
authors.initials: K
authors.lastname: Sun
authors.forename: Qiu-Dong
authors.initials: QD
authors.lastname: Zhao
authors.forename: Xu-Qin
authors.initials: XQ
authors.lastname: Xie
authors.forename: Yu-Jiao
authors.initials: YJ
authors.lastname: Song
authors.forename: Meng-Chao
authors.initials: MC
authors.lastname: Wu
authors.forename: Li-Xin
authors.initials: LX
authors.lastname: Wei
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins / Q000037:antagonists & inhibitors; D001343:Autophagy / Q000187:drug effects / Q000502:physiology*; D000071186:Beclin-1; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology; D005472:Fluorouracil / Q000494:pharmacology; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008565:Membrane Proteins / Q000037:antagonists & inhibitors; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation
chemical_list: D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; C491997:BECN1 protein, human; D000071186:Beclin-1; D008565:Membrane Proteins; C025946:3-methyladenine; D000225:Adenine; D002945:Cisplatin; D005472:Fluorouracil