Inhibition of the RAS oncoprotein reduces proliferation of hepatocytes in vitro and in vivo in rats

Alain da Silva Morais , Alain Saliez , Isabelle Leclercq , Yves Horsmans , Peter Stärkel (1)

1 Gastroenterology

Ras oncoproteins are likely implicated in normal and malignant cell growth in various organs. Inhibition of Ras interferes with cell proliferation of non-hepatic cells in vitro and in vivo. A potential role for Ras in normal and malignant hepatocytes proliferation prompted us to evaluate the impact of Ras inhibition by S-Farnesylthiosalicylic acid (FTS) on hepatocyte proliferation in vitro on the human hepatic tumour cell line Hep G2 and in vivo after partial hepatectomy (PH) in rats. Rats were administered FTS intraperitoneally (1,8, 16h after PH) and sacrificed 12, 24 and 48 hours after PH. Cell proliferation, the MAPkinase pathway and cell cycle effectors (cyclin D, E, Cdk2, Cdk4) were assessed in FTS treated rats compared to controls. FTS significantly decreased overall cell count, PCNA expression and BrdU incorporation of HepG2 cells after 7 days of culture. FTS treatment significantly reduced BrdU incorporation and PCNA expression in hepatocytes after PH. Unlike control rats, cell membrane expression of ras was reduced in FTS-treated animals after PH resulting in decreased Raf membrane recruitment and phosporylation and in diminished phosphorylation of Erk1/2. The anti-proliferative effect of FTS was linked to a reduced expression and activity of the cyclin E/Cdk2 complex without affecting cyclin D and Cdk4. Ras inhibition by FTS significantly reduced proliferation of HepG2 cells and of normal hepatocytes after a strong and highly synchronized proliferation stimulus elicited by PH. The inhibitory effect was at least partially mediated by inhibition of Ras-Raf-MAPkinase signalling. It seems worthwhile to evaluate the impact of Ras inhibition on the development of hepatocarcinomas in vivo in adequate animal models.

Mots clés: Medicine

Alain da Silva Morais, Alain Saliez, Isabelle Leclercq, Yves Horsmans, Peter Stärkel. Inhibition of the RAS oncoprotein reduces proliferation of hepatocytes in vitro and in vivo in rats. Clinical Science, 2007, 114 (1), pp.73-83. ⟨10.1042/CS20070152⟩. ⟨hal-00479383⟩