title: AZD8055 induces cell death associated with autophagy and activation of AMPK in hepatocellular carcinoma.
abstract: AZD8055 is a potent inhibitor of mTORC1 and mTOR2 and shows inhibitory effects in several types of cancer cells in vitro and in vivo. However, the effect of AZD8055 on hepatocellular carcinoma (HCC) cells has not been studied. We report that AZD8055 inhibits cell proliferation and colony formation of Hep3B and Huh7 cells but does not cause PARP cleavage, or caspase activation, suggesting that classical apoptosis is not its main mechanism of cell death. By contrast, AZD8055-induced cell death was associated with several characteristics of autophagy, including an increase in acidic vesicular organelle content, conversion of cytosolic LC3-I to membrane-bound LC3-II and elevation of the levels of Atg-5/12, BECN1 and LC3-II. Inhibition of autophagy by 3-methyladenine (3-MA) partially inhibited AZD8055-induced cell death. Furthermore, AZD8055 caused the activation of AMPK and co-treatment with the AMPK inhibitor dorsomorphin also caused a partial but significant reduction of AZD8055-induced cell death. In conclusion, AZD8055-induced HCC cell death is associated with induction of autophagy and activation of AMPK.
authors.affiliation: Laboratory of Hepatobiliary Surgery, Affiliated Hospital of Guangdong Medical College, Zhanjiang, Guangdong 524001, P.R. China.
authors.forename: Min
authors.initials: M
authors.lastname: Hu
authors.affiliation: Laboratory of Hepatobiliary Surgery, Affiliated Hospital of Guangdong Medical College, Zhanjiang, Guangdong 524001, P.R. China.
authors.forename: Haili
authors.initials: H
authors.lastname: Huang
authors.affiliation: Institute of Genetic Engineering, Southern Medical University, Guangzhou, Guangdong 510515, P.R. China.
authors.forename: Rui
authors.initials: R
authors.lastname: Zhao
authors.affiliation: Clinical Research Center, Affiliated Hospital of Guangdong Medical College, Zhanjiang, Guangdong 524001, P.R. China.
authors.forename: Peng
authors.initials: P
authors.lastname: Li
authors.affiliation: Laboratory of Hepatobiliary Surgery, Affiliated Hospital of Guangdong Medical College, Zhanjiang, Guangdong 524001, P.R. China.
authors.forename: Mingyi
authors.initials: M
authors.lastname: Li
authors.affiliation: Laboratory of Hepatobiliary Surgery, Affiliated Hospital of Guangdong Medical College, Zhanjiang, Guangdong 524001, P.R. China.
authors.forename: Huilai
authors.initials: H
authors.lastname: Miao
authors.affiliation: Laboratory of Hepatobiliary Surgery, Affiliated Hospital of Guangdong Medical College, Zhanjiang, Guangdong 524001, P.R. China.
authors.forename: Nianping
authors.initials: N
authors.lastname: Chen
authors.affiliation: Laboratory of Hepatobiliary Surgery, Affiliated Hospital of Guangdong Medical College, Zhanjiang, Guangdong 524001, P.R. China.
authors.forename: Ming
authors.initials: M
authors.lastname: Chen
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000225:Adenine / Q000031:analogs & derivatives / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins / Q000096:biosynthesis; D001343:Autophagy / Q000187:drug effects*; D000071192:Autophagy-Related Protein 12; D000071187:Autophagy-Related Protein 5; D000071186:Beclin-1; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy*; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy*; D000076222:Mechanistic Target of Rapamycin Complex 1; D000076225:Mechanistic Target of Rapamycin Complex 2; D008565:Membrane Proteins / Q000096:biosynthesis; D008869:Microtubule-Associated Proteins / Q000096:biosynthesis / Q000378:metabolism; D009025:Morpholines / Q000494:pharmacology*; D046912:Multiprotein Complexes / Q000037:antagonists & inhibitors; D010766:Phosphorylation / Q000187:drug effects; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D025841:Small Ubiquitin-Related Modifier Proteins / Q000096:biosynthesis; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors
chemical_list: C466624:ATG12 protein, human; C502778:ATG5 protein, human; D051017:Apoptosis Regulatory Proteins; D000071192:Autophagy-Related Protein 12; D000071187:Autophagy-Related Protein 5; C491997:BECN1 protein, human; D000071186:Beclin-1; C477012:MAP1LC3A protein, human; D008565:Membrane Proteins; D008869:Microtubule-Associated Proteins; D009025:Morpholines; D046912:Multiprotein Complexes; D025841:Small Ubiquitin-Related Modifier Proteins; C025946:3-methyladenine; C546624:(5-(2,4-bis((3S)-3-methylmorpholin-4-yl)pyrido(2,3-d)pyrimidin-7-yl)-2-methoxyphenyl)methanol; C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; D000076222:Mechanistic Target of Rapamycin Complex 1; D000076225:Mechanistic Target of Rapamycin Complex 2; D058570:TOR Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases; D020169:Caspases; D000225:Adenine