Effects of apicidin, a histone deacetylase inhibitor, on the regulation of apoptosis in H-ras-transformed breast epithelial cells

Abstract

Abstract. The cellular susceptibility of cancer cells to histone deacetylase (HDAC) inhibitors is increased by the etopic expression of oncogenic Ras. However, the ability of HDAC inhibitors to regulate the apoptotic pathway in human breast cancer cells is still not completely understood. In this study, the anti-proliferative effects of apicidin were compared in Hras-transformed human breast epithelial (MCF10A-ras) and non-transformed epithelial (MCF10A) cells. MCF10A-ras cells showed a significantly higher growth rate than MCF10A cells. Apicidin significantly increased the levels of acetylated histone H3 and H4 in both cell lines. Western blot analysis and flow cytometry were used to determine if the anti-proliferative effects of apicidin in MCF10A and MCF10A-ras cells could be mediated by modulating the cell cycle. Apicidin attenuated the expression of cyclin E and CDK2 in MCF10A cells, decreased cyclin D1 and cyclin E levels in MCF10A-ras cells, and increased the levels of CDK inhibitors, p21WAF1/Cip1 and p27Kip1 , in both cell lines. Notably, the levels of hyperphosphorylation of the Rb protein levels were lower in the MCF10A-ras cells after apicidin treatment. Studies on the regulation of apoptosis showed that apicidin induces the upregulation of p53 and the downstream activation of ERK in MCF10A-ras cells. The up-regulation of p53 promoted Bax expression leading to activation of caspases-9 and -6, and eventually to apoptosis in MCF10A-ras cells. In addition, apicidin significantly increased the levels of ERK1/2 phosphorylation in MCF10A-ras cells. Therefore, the apicidinmediated ERK pathway appears to play an important role in modulating the pro-apoptotic pathway in MCF10A-ras cells.

Acid-induced cell injury and death in lung epithelial cells is associated with the activation of mitogen-activated protein kinases

“…Thus, the p-38 MAPK pathway is suggested to be involved in HCl-induced cell apoptosis. Involvement of the ERK pathway in cell proliferation and apoptosis has previously been reported (28). In the present study, no change in the viability of BEAS-2B cells or the expression of apoptotic proteins was observed using ERK inhibitors.…”

Histone deacetylase inhibitors induce CXCR4 mRNA but antagonize CXCR4 migration

“…Park et al suggest that apicidin induced cell cycle arrest by activation of the ERK pathway in Ras-transformed breast epithelial cells. 41 Abnormal retention of p-ERK in cytoplasm after SW620, express elevated basal CXCR4 levels. This variable gene response to romidepsin is similar to that observed for ABCG2, a drug transporter not involved in romidepsin efflux.…”

Valproic acid (VPA), a histone deacetylase (HDAC) inhibitor, diminishes lymphoproliferation in the Fas -deficient MRL/lpr−/− murine model of autoimmune lymphoproliferative syndrome (ALPS)

“…Since approximately 50% of children with ALPS have refractory autoimmune cytopenias and undergo splenectomy, placing them at increased risk of life-threatening pneumococcal and meningococcal bacteremia, we sought a safe and effective medication to control lymphoproliferation and hypersplenism. Several histone deacetylase (HDAC) inhibitors, including apicidin[17, 18], sodium butyrate[19], and psammaplin A[20] induce apoptosis of various tumor cells. Two HDAC inhibitors, trichostatin A (TSA) and suberonylanilide hydroxamic acid (SAHA) have been used to treat MRL/lpr−/− mice.…”