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首页> 外文期刊>Biochemical Pharmacology >Trichostatin A sensitizes human ovarian cancer cells to TRAIL-induced apoptosis by down-regulation of c-FLIPL via inhibition of EGFR pathway.
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Trichostatin A sensitizes human ovarian cancer cells to TRAIL-induced apoptosis by down-regulation of c-FLIPL via inhibition of EGFR pathway.

机译：曲古抑菌素A通过抑制EGFR通路而下调c-FLIPL，从而使人卵巢癌细胞对TRAIL诱导的细胞凋亡敏感。

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摘要

TRAIL-resistant cancer cells can be sensitized to TRAIL by combination therapy. In this study, we investigated the effect of trichostatin A (TSA), a histone deacetylase inhibitor, to overcome the TRAIL resistance in human ovarian cancer cells. Co-treatment of human ovarian cancer cells with TSA and TRAIL synergistically inhibited cell proliferation and induced apoptosis. The combined treatment of ovarian cancer SKOV3 cells with TSA and TRAIL significantly activated caspase-8 and truncated Bid, resulting in the cytosolic accumulation of cytochrome c as well as the activation of caspase-9 and -3. Moreover, we found that down-regulation of c-FLIP(L) might contribute to TSA-mediated sensitization to TRAIL-induced apoptosis in SKOV3 cells, and this result was supported by showing that down- or up-regulation of c-FLIP(L) with transfection of siRNA or plasmid sensitized or made SKOV3 cells resistant to TRAIL-induced apoptosis, respectively. TSA or co-treatment with TSA alone and TRAIL also resulted in down-regulation of EGFR1/2 and dephosphorylation of its downstream targets, AKT and ERK. Treatment of SKOV3 cells with PKI-166 (EGFR1/2 inhibitor), LY294002 (AKT inhibitor), and PD98059 (ERK inhibitor) decreased c-FLIP(L) expression and co-treatment with TRAIL further reduced the level of c-FLIP(L,) respectively, as did TSA. Collectively, our data suggest that TSA-mediated sensitization of ovarian cancer cells to TRAIL is closely correlated with down-regulation of c-FLIP(L) via inhibition of EGFR pathway, involving caspase-dependent mitochondrial apoptosis, and combination of TSA and TRAIL may be an effective strategy for treating TRAIL-resistant human ovarian cancer cells.
机译：TRAIL耐药癌细胞可以通过联合疗法对TRAIL敏感。在这项研究中，我们调查了组蛋白脱乙酰基酶抑制剂曲古抑菌素A（TSA）克服人类卵巢癌细胞对TRAIL的抵抗作用。 TSA和TRAIL共同治疗人卵巢癌细胞可协同抑制细胞增殖并诱导细胞凋亡。用TSA和TRAIL联合治疗卵巢癌SKOV3细胞可显着激活caspase-8和截短的Bid，从而导致细胞色素c的胞浆积聚以及caspase-9和-3的激活。此外，我们发现c-FLIP（L）的下调可能有助于TSA介导的TRAIL诱导的SKOV3细胞凋亡的敏化作用，这一结果得到了c-FLIP（下调或上调）的支持。 L）分别转染了对TRAIL诱导的细胞凋亡具有敏感性的siRNA或转染的SKOV3细胞。 TSA或仅与TSA和TRAIL共同治疗也会导致EGFR1 / 2的下调以及其下游靶标AKT和ERK的去磷酸化。用PKI-166（EGFR1 / 2抑制剂），LY294002（AKT抑制剂）和PD98059（ERK抑制剂）处理SKOV3细胞可降低c-FLIP（L）表达，并与TRAIL共同处理可进一步降低c-FLIP（ L）和TSA一样。总体而言，我们的数据表明，TSA介导的卵巢癌细胞对TRAIL的敏感性与c-FLIP（L）的下调（通过抑制EGFR途径）密切相关，涉及caspase依赖性线粒体凋亡，TSA和TRAIL的组合可能是治疗TRAIL耐药的人卵巢癌细胞的有效策略。

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