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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.
Abbreviations
| ERK | = | extracellular signal-regulated kinase |
| HCC | = | Hepatocellular Carcinoma |
| mTOR | = | mammalian target of rapamycin |
| PI3K | = | phosphatidylinositol-3-kinase |
| PICS | = | PTEN-Induced Cellular Senescence |
| PTEN | = | Phosphatase and tensin homolog |
| SA-β-GAL | = | senescence-associated β-galactosidase |
| SHP1 | = | Src homology region 2 domain-containing phosphatase-1 |
Disclosure of potential conflicts of interest
No potential conflicts of interest were disclosed.
Acknowledgments
We thank Prof. Pier P. Pandolfi and Dr. John G. Clohessy for their usefully suggestions in the use of VO-OHpic in the in vivo experiments. The authors are grateful to Drs. Caterina Di Sano and Andreina Bruno for flow cytometric analysis, and Mrs. Antonina Azzolina for the technical support provided.
Funding
This work was supported in part by grants from the Italian “Ministero dell'Istruzione, dell'Università e della Ricerca (Ministry for Education, Universities and Research) – MIUR FIRB-MERIT n. RBNE08YYBM to M.C. and G.M; M.C. was also supported in part by a grant to the CNR from the Italian Ministry of Economy and Finance for the Project FaReBio di Qualità.
