title: Potentiation of the anticancer effects of everolimus using a dual mTORC1/2 inhibitor in hepatocellular carcinoma cells.
abstract: There is lots of evidence to support the critical involvement of mTOR signaling in the carcinogenesis of hepatocellular carcinoma (HCC). However, it has not been determined how the roles of individual mTORC1 and mTORC2 inhibitors played in the HCC therapeutics. We thus compared the effects of everolimus, Ku0063794, and a combination of the two therapies on HCC cells, using various in vitro studies (HepG2, Hep3B, and Huh7 cells), ex vivo culturing of HCC tissues obtained from patients, and the in vivo mouse xenograft model of HCC cells. Our in vitro, ex vivo, and in vivo experiments consistently demonstrated that everolimus and Ku0063794 combination therapy was superior to individual monotherapies, as manifested by higher reduction of proliferation, migration, and invasion of HCC cells, and the higher inhibition of EMT process as well. Although individual monotherapies could not inhibit SIRT1 (positive regulator of EMT) expression, the combination therapy significantly inhibited SIRT1 expression. However, overexpression of SIRT1 mitigated the EMT-inhibiting effect of the combination therapy, suggesting that the combination therapy inhibits the EMT by way of suppressing SIRT1 expression. Therefore, when considering everolimus as an anti-HCC agent, the improved anticancer effects provided by combining it with an inhibitor of both mTORC1 and mTORC2 should be recognized.
authors.affiliation: Department of Pathology, Daejeon St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.
authors.forename: Jong-Ok
authors.initials: JO
authors.lastname: Kim
authors.affiliation: Department of Surgery, Uijeongbu St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.
authors.forename: Kee-Hwan
authors.initials: KH
authors.lastname: Kim
authors.affiliation: Department of Surgery, Chungnam National University Hospital, Daejeon, Republic of Korea.
authors.forename: In Sang
authors.initials: IS
authors.lastname: Song
authors.affiliation: Department of Surgery, Chungnam National University Hospital, Daejeon, Republic of Korea.
authors.forename: Kwang-Sik
authors.initials: KS
authors.lastname: Cheon
authors.affiliation: Department of Surgery, Daejeon St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.
authors.forename: Ok-Hee
authors.initials: OH
authors.lastname: Kim
authors.affiliation: Department of Surgery, Daejeon St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.
authors.forename: Sang Chul
authors.initials: SC
authors.lastname: Lee
authors.affiliation: Department of Surgery, Daejeon St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.
authors.forename: Sang Kuon
authors.initials: SK
authors.lastname: Lee
authors.affiliation: Department of Surgery, Daejeon St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.
authors.forename: Say-June
authors.initials: SJ
authors.lastname: Kim
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D004357:Drug Synergism; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects / Q000235:genetics; D000068338:Everolimus / Q000494:pharmacology*; D015870:Gene Expression; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D000076222:Mechanistic Target of Rapamycin Complex 1 / Q000037:antagonists & inhibitors*; D000076225:Mechanistic Target of Rapamycin Complex 2 / Q000037:antagonists & inhibitors*; D051379:Mice; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D056564:Sirtuin 1 / Q000235:genetics / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D000068338:Everolimus; D000076222:Mechanistic Target of Rapamycin Complex 1; D000076225:Mechanistic Target of Rapamycin Complex 2; C447939:SIRT1 protein, human; D056564:Sirtuin 1
keywords: Ku0063794; SIRT1; everolimus; hepatocellular carcinoma; mTOR inhibitor