Inhibition of EGFR/PI3K/AKT cell survival pathway promotes TSA's effect on cell death and migration in human ovarian cancer cells.

Trichostatin A (TSA), a hydroxamate-type inhibitor of mammalian histone deacetylases, is emerging as one of a potentially new class of anticancer agents. TSA is known to act by promoting the acetylation of histones, leading to uncoiling of chromatin and activation of a variety of genes implicated in the regulation of cell survival, proliferation, differentiation, and apoptosis. In addition, there is an increasing appreciation of the fact that TSA may act through mechanisms other than induction of histone acetylation. Accumulated experimental data indicate that TSA activates phosphatidyl inositol-3-kinase (PI3K)/AKT signaling. Using human ovarian cancer cell line Caov3 cells, we observed that TSA induced cell death in a time- and dose-dependent manner and also inhibited cell migration. TSA transiently activated EGFR tyrosine phosphorylation and AKT activation in a time- and dose-dependent manner, which had been inhibited by EGFR inhibitor PD153035 and PI3 kinase inhibitor LY294002. We also observed that TSA transiently induced survivin expression that had been inhibited by PD153035 and LY294002, suggesting that TSA-induced survivin expression is mediated by EGFR/PI3 kinase pathway. Combination of EGFR inhibitor 153035 or PI3 kinase inhibitor LY294002 with TSA enhanced TSA-induced cell death and TSA reduction of cell migration. Collectively, our data demonstrate that TSA transiently activated EGFR/PI3K/AKT cell survival pathway, leading to expression of survivin. Inhibition of this pathway enhanced TSA-induced cell death and inhibited cell migration. Our data suggest that combination of EGFR/PI3K/AKT cell survival pathway inhibitors with TSA be a better approach to ovarian cancer treatment.