title: A PTEN inhibitor displays preclinical activity against hepatocarcinoma cells.
abstract: Phosphatase and tensin homolog (PTEN) gene is considered a tumor suppressor gene. However, PTEN mutations rarely occur in hepatocellular carcinoma (HCC), whereas heterozygosity of PTEN, resulting in reduced PTEN expression, has been observed in 32-44% of HCC patients. In the present study, we investigated the effects of the small molecule PTEN inhibitor VO-OHpic in HCC cells. VO-OHpic inhibited cell viability, cell proliferation and colony formation, and induced senescence-associated β-galactosidase activity in Hep3B (low PTEN expression) and to a lesser extent in PLC/PRF/5 (high PTEN expression) cells, but not in PTEN-negative SNU475 cells. VO-OHpic synergistically inhibited cell viability when combined with PI3K/mTOR and RAF/MEK/ERK pathway inhibitors, but only in Hep3B cells, and significantly inhibited tumor growth in nude mice bearing xenografts of Hep3B cells. Therefore, we demonstrated for the first time that VO-OHpic inhibited cell growth and induced senescence in HCC cells with low PTEN expression, and that the combination of VO-OHpic with PI3K/mTOR and RAF/MEK/ERK inhibitors resulted in a more effective tumor cell kill. Our findings, hence, provide proof-of-principle evidence that pharmacological inhibition of PTEN may represent a promising approach for HCC therapy in a subclass of patients with a low PTEN expression.
authors.affiliation: a Institute of Biomedicine and Molecular Immunology "Alberto Monroy,", National Research Council (CNR) , Palermo , Italy.
authors.forename: Giuseppa
authors.initials: G
authors.lastname: Augello
authors.affiliation: b Istituto Zooprofilattico Sperimentale della Sicilia "A Mirri,", Area Diagnostica Specialistica, Laboratorio di Istopatologia ed Immunoistochimica , Palermo , Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Puleio
authors.affiliation: a Institute of Biomedicine and Molecular Immunology "Alberto Monroy,", National Research Council (CNR) , Palermo , Italy.
authors.forename: Maria Rita
authors.initials: MR
authors.lastname: Emma
authors.affiliation: a Institute of Biomedicine and Molecular Immunology "Alberto Monroy,", National Research Council (CNR) , Palermo , Italy.
authors.forename: Antonella
authors.initials: A
authors.lastname: Cusimano
authors.affiliation: b Istituto Zooprofilattico Sperimentale della Sicilia "A Mirri,", Area Diagnostica Specialistica, Laboratorio di Istopatologia ed Immunoistochimica , Palermo , Italy.
authors.forename: Guido R
authors.initials: GR
authors.lastname: Loria
authors.affiliation: c Department of Microbiology and Immunology , Brody School of Medicine at East Carolina University , Greenville , NC , USA.
authors.forename: James A
authors.initials: JA
authors.lastname: McCubrey
authors.affiliation: a Institute of Biomedicine and Molecular Immunology "Alberto Monroy,", National Research Council (CNR) , Palermo , Italy.|d Biomedical Department of Internal Medicine and Specialties (DiBiMIS), University of Palermo , Palermo , Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Montalto
authors.affiliation: a Institute of Biomedicine and Molecular Immunology "Alberto Monroy,", National Research Council (CNR) , Palermo , Italy.
authors.forename: Melchiorre
authors.initials: M
authors.lastname: Cervello
mesh_terms: D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D051379:Mice; D009942:Organometallic Compounds / Q000008:administration & dosage*; D051059:PTEN Phosphohydrolase / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000235:genetics; D023041:Xenograft Model Antitumor Assays
chemical_list: D009942:Organometallic Compounds; D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases; D058570:TOR Serine-Threonine Kinases; C000600334:VO-OHpic; C546842:MTOR protein, human; C494929:PTEN protein, human
keywords: AKT; HCC; PTEN; Sorafenib; VO-OHpic; senescence