title: Autophagy inhibition sensitizes hepatocellular carcinoma to the multikinase inhibitor linifanib.
abstract: Autophagy is a critical survival pathway for cancer cells under conditions of stress. Thus, induction of autophagy has emerged as a drug resistance mechanism. This study is to determine whether autophagy is activated by a novel multikinase inhibitor linifanib, thereby impairing the sensitivity of hepatocellular carcinoma (HCC) cells to this targeted therapy. Here, we found that linifanib induced a high level of autophagy in HCC cells, which was accompanied by suppression of phosphorylation of PDGFR-β and its downstream Akt/mTOR and Mek/Erk signaling pathways. Cell death induced by linifanib was greatly enhanced after autophagy inhibition by the pharmacological inhibitors or siRNAs against autophagy related genes, ATG5 and ATG7, in vitro. Moreover, HCQ, an FDA-approved drug used to inhibit autophagy, could significantly augment the anti-HCC effect of linifanib in a mouse xenograft model. In conclusion, linifanib can induce cytoprotective autophagy by suppression of PDGFR-β activities in HCC cells. Thus, autophagy inhibition represents a promising approach to improve the efficacy of linifanib in the treatment of HCC patients.
authors.affiliation: Department of Medical Oncology, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.
authors.forename: Hongming
authors.initials: H
authors.lastname: Pan
authors.affiliation: Department of Medical Oncology, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.
authors.forename: Zhanggui
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Department of Medical Oncology, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.
authors.forename: Liming
authors.initials: L
authors.lastname: Jiang
authors.affiliation: Department of Medical Oncology, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.
authors.forename: Xinbing
authors.initials: X
authors.lastname: Sui
authors.affiliation: Department of Medical Oncology, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.
authors.forename: Liangkun
authors.initials: L
authors.lastname: You
authors.affiliation: Department of Medical Oncology, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.
authors.forename: Jiawei
authors.initials: J
authors.lastname: Shou
authors.affiliation: Department of Medical Oncology, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.
authors.forename: Zhao
authors.initials: Z
authors.lastname: Jing
authors.affiliation: Laboratory of Cancer Biology; Institute of Clinical Science, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.
authors.forename: Jiansheng
authors.initials: J
authors.lastname: Xie
authors.affiliation: Cancer Institute, The Second Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.
authors.forename: Weiting
authors.initials: W
authors.lastname: Ge
authors.affiliation: Department of General Surgery, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.
authors.forename: Xiujun
authors.initials: X
authors.lastname: Cai
authors.affiliation: Division of Molecular Diabetes Research, Department of Diabetes and Metabolic Diseases Research, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA.
authors.forename: Wendong
authors.initials: W
authors.lastname: Huang
authors.affiliation: Department of Medical Oncology, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.
authors.forename: Weidong
authors.initials: W
authors.lastname: Han
mesh_terms: D000818:Animals; D001343:Autophagy / Q000235:genetics*; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D002470:Cell Survival / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D056945:Hep G2 Cells; D006801:Humans; D007191:Indazoles / Q000008:administration & dosage*; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D051379:Mice; D010671:Phenylurea Compounds / Q000008:administration & dosage*; D015398:Signal Transduction / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D007191:Indazoles; D010671:Phenylurea Compounds; C513486:linifanib