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Abstract
BackgroundDysregulation of epidermal growth factor and insulin-like growth factor signaling play important roles in human hepatocellular carcinoma (HCC), leading to frequent activation of their downstream targets, the ras/raf/extracellular signal-regulated kinase (ERK) and the phosphoinositide 3-kinase (PI3K)/Akt/mammalian Target of Rapamycin (mTOR) pathways. Salirasib is an S-prenyl-cysteine analog that has been shown to block ras and/or mTOR activation in several non hepatic tumor cell lines. We investigated in vitro the effect of salirasib on cell growth as well as its mechanism of action in human hepatoma cell lines (HepG2, Huh7, and Hep3B) and its in vivo effect in a subcutaneous xenograft model with HepG2 cells.ResultsSalirasib induced a time and dose dependent growth inhibition in hepatocarcinoma cells through inhibition of proliferation and partially through induction of apoptosis. A 50 percent reduction in cell growth was obtained in all three cell lines at a dose of 150 μM when they were cultured with serum. By contrast, salirasib was more potent at reducing cell growth after stimulation with EGF or IGF2 under serum-free conditions, with an IC50 ranging from 60 μM to 85 μM. The drug-induced anti-proliferative effect was associated with downregulation of cyclin A and to a lesser extent of cyclin D1, and upregulation of p21 and p27. Apoptosis induction was related to a global pro-apoptotic balance with caspase 3 activation, cytochrome c release, death receptor upregulation, and a reduced mRNA expression of the apoptosis inhibitors cFLIP and survivin. These effects were associated with ras downregulation and mTOR inhibition, without reduction of ERK and Akt activation. In vivo, salirasib reduced tumour growth from day 5 onwards. After 12 days of treatment, mean tumor weight was diminished by 56 percent in the treated animals.ConclusionsOur results show for the first time that salirasib inhibits the growth of human hepatoma cell lines through inhibition of proliferation and induction of apoptosis, which is associated with ras and mTOR inhibition. The therapeutic potential of salirasib in human HCC was further confirmed in a subcutaneous xenograft model.
Highlights
Dysregulation of epidermal growth factor and insulin-like growth factor signaling play important roles in human hepatocellular carcinoma (HCC), leading to frequent activation of their downstream targets, the ras/ raf/extracellular signal-regulated kinase (ERK) and the phosphoinositide 3-kinase (PI3K)/Akt/mammalian Target of Rapamycin pathways
As fetal bovine serum (FBS) is a cocktail of growth factors and cytokines recruiting multiple receptors, we hypothesized that salirasib would be more effective in reducing cell growth in serum starved cells that were selectively exposed to epidermal growth factor (EGF) or IGF2 only
We observed that salirasib treatment elicited a dose-dependent decrease in cell viability in all 3 cell lines that was more pronounced in both EGF- and IGF2-stimulated cells than in FBS-stimulated cells
Summary
Dysregulation of epidermal growth factor and insulin-like growth factor signaling play important roles in human hepatocellular carcinoma (HCC), leading to frequent activation of their downstream targets, the ras/ raf/extracellular signal-regulated kinase (ERK) and the phosphoinositide 3-kinase (PI3K)/Akt/mammalian Target of Rapamycin (mTOR) pathways. Altered intracellular signaling elicited by epidermal growth factor (EGF), insulin-like growth factor (IGF) and Vascular Endothelial Growth Factor have been involved in the pathogenesis of HCC Inhibitors of their receptors are under intense investigation. In non hepatic epithelial tumor cell lines, inhibition of EGFR or IGF-1R individually promotes activation of the reciprocal receptor [5] and IGF-2 overexpression has been involved in the resistance of HCC to EGFR inhibition in a rat model [6] Treatment interfering with both receptors could represent a better strategy to treat this disease. Targeting one or several of their downstream signaling pathways could be an elegant way to block growth factor signaling Among those, both ras-raf-MEK-ERK and PI3K-Akt-mTOR pathways are activated upon EGFR and IGF-1R stimulation. While ras activation upon EGFR stimulation induces PI3K activation [7], IGF-1R is able to activate the PI3K-Akt-mTOR pathway independently of ras [8]
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