title: Autophagy prevention sensitizes AKTi-1/2-induced anti-hepatocellular carcinoma cell activity in vitro and in vivo.
abstract: Molecule-targeted therapy has become the research focus for hepatocellular carcinoma (HCC). Persistent PI3K-AKT activation is often detected in HCC, representing a valuable oncotarget for treatment. Here, we tested the anti-HCC activity by a potent AKT inhibitor: AKT inhibitor 1/2 (AKTi-1/2). In both established (HepG2 and Huh-7) and primary human HCC cells, treatment with AKTi-1/2 inhibited cell survival and proliferation, but induced cell apoptosis. AKTi-1/2 blocked AKT-mTOR activation, yet simultaneously provoked cytoprotective autophagy in HCC cells. The latter was evidenced by ATG-5 and Beclin-1 upregulation, p62 downregulation as well as LC3B-GFP puncta formation. Autophagy inhibition, via pharmacological inhibitors (3-methyladenine, ammonium chloride, and bafilomycin A1) or Beclin-1 siRNA knockdown, significantly potentiated AKTi-1/2-induced HepG2 cell death and apoptosis. In nude mice, AKTi-1/2 intraperitoneal injection inhibited HepG2 tumor growth. Significantly, its anti-tumor activity in vivo was further sensitized when combined with Beclin-1 shRNA knockdown in HepG2 tumors. Together, these results demonstrate that autophagy activation serves as a main resistance factor of AKTi-1/2 in HCC cells. Autophagy prevention therefore sensitizes AKTi-1/2-induced anti-HCC activity in vitro and in vivo.
authors.affiliation: Department of Hepatobiliary & Pancreatic Surgery, Xiangya Hospital, Central South University, Changsha, China.
authors.forename: Qi
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: National Hepatobiliary & Enteric Surgery Research Center, Xiangya Hospital, Central South University, Changsha, China.
authors.forename: Manyi
authors.initials: M
authors.lastname: Yang
authors.affiliation: Department of Hepatobiliary & Pancreatic Surgery, Xiangya Hospital, Central South University, Changsha, China.
authors.forename: Zhan
authors.initials: Z
authors.lastname: Qu
authors.affiliation: National Hepatobiliary & Enteric Surgery Research Center, Xiangya Hospital, Central South University, Changsha, China.
authors.forename: Jixiang
authors.initials: J
authors.lastname: Zhou
authors.affiliation: Department of Ultrasonography, Xiangya Hospital, Central South University, Changsha, China. Electronic address: jiangqinys@yeah.net.
authors.forename: Qin
authors.initials: Q
authors.lastname: Jiang
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D001343:Autophagy / Q000187:drug effects*; D001596:Benzylamines / Q000009:adverse effects*; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D004357:Drug Synergism; D005260:Female; D056945:Hep G2 Cells; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D058990:Molecular Targeted Therapy / Q000379:methods; D011810:Quinoxalines / Q000009:adverse effects*; D016896:Treatment Outcome
chemical_list: C501521:Akt-I-1,2 compound; D000970:Antineoplastic Agents; D001596:Benzylamines; D011810:Quinoxalines
keywords: AKT; AKTi-1/2; Autophagy and chemo-sensitization; Hepatocellular carcinoma