The effect of S-farnesyl-thiosalicylic acid (FTS, salirasib) on proliferation, apoptosis and signalling pathways in human hepatocarcinoma cell lines

Abstract

Hepatocarcinoma is a frequent and lethal cancer with limited treatment options at an advanced stage. Ras activation seems to be a constant and early event in human hepatocarcinogenesis. Previous work of our team showed that inhibition of Ras by salirasib – an S-prenylcysteine analogue that inhibits Ras by competing with its membrane docking sites – prevents the development of hepatocarcinomas in a rat model of chemically-induced hepatocarcinogenesis. In the present work, we evaluated the anti-tumour activity of salirasib in human hepatocarcinoma cell lines in vitro and in vivo in a subcutaneous xenograft model. We showed that salirasib reduces the growth of HepG2, Huh7 and Hep3B cells, essentially through inhibition of cell proliferation. The effect on cell growth was associated with Ras inhibition, although ERK and Akt phosphorylation was not affected. Furthermore, we found that salirasib directly interfered with mTOR activation. Salirasib also induced a pro-apoptotic phenotype with upregulation of death receptors and downregulation of endogenous apoptosis inhibitors, while true induction of apoptosis was inconstant. Finally, we showed that salirasib reduces tumour growth in a subcutaneous HepG2 xenograft model. Taking advantage of these results indicating that hepatocarcinoma cell lines are possibly primed for apoptosis, we next showed that pre-treatment with salirasib sensitizes hepatocarcinoma cells to TRAIL-induced apoptosis involving both the intrinsic and the extrinsic pathways. Salirasib elicited a significant downregulation of survivin that was associated with apoptosis induction. Using the survivin inhibitor YM155, we further demonstrated that inhibition of survivin is sufficient to sensitize hepatocarcinoma cells to TRAIL-induced apoptosis. In addition, the action of TRAIL was dependent on DR5. Importantly, neither salirasib, TRAIL, nor the combination of both of them induced apoptosis in normal human hepatocytes.(MED - Sciences médicales) -- UCL, 201