Zhou Changlin, Qiu Lihua, Sun Yun, Healey Sarah, Wanebo Harold, Kouttab Nicola, Di Wen, Yan Bingfang, Wan Yinsheng
Department of Biology, Providence College, RI 02918, USA.
Int J Oncol. 2006 Jul;29(1):269-78.
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.
曲古抑菌素A（TSA）是一种异羟肟酸型哺乳动物组蛋白脱乙酰酶抑制剂，正逐渐成为一类潜在的新型抗癌药物。已知TSA通过促进组蛋白乙酰化发挥作用，导致染色质解旋并激活多种与细胞存活、增殖、分化和凋亡调控相关的基因。此外，人们越来越认识到TSA可能通过诱导组蛋白乙酰化以外的机制发挥作用。积累的实验数据表明，TSA可激活磷脂酰肌醇-3-激酶（PI3K）/AKT信号通路。使用人卵巢癌细胞系Caov3细胞，我们观察到TSA以时间和剂量依赖性方式诱导细胞死亡，并抑制细胞迁移。TSA以时间和剂量依赖性方式短暂激活表皮生长因子受体（EGFR）酪氨酸磷酸化和AKT激活，而这已被EGFR抑制剂PD153035和PI3激酶抑制剂LY294002所抑制。我们还观察到TSA短暂诱导survivin表达，而这已被PD153035和LY294002所抑制，表明TSA诱导的survivin表达是由EGFR/PI3激酶途径介导的。EGFR抑制剂153035或PI3激酶抑制剂LY294002与TSA联合使用可增强TSA诱导的细胞死亡以及TSA对细胞迁移的抑制作用。总体而言，我们的数据表明TSA短暂激活EGFR/PI3K/AKT细胞存活途径，导致survivin表达。抑制该途径可增强TSA诱导的细胞死亡并抑制细胞迁移。我们的数据表明，将EGFR/PI3K/AKT细胞存活途径抑制剂与TSA联合使用可能是治疗卵巢癌的更好方法。
