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ERK inhibition enhances TSA-induced gastric cancer cell apoptosis via NF-κB-dependent and Notch-independent mechanism

机译：ERK抑制通过NF-κB依赖性和Notch依赖性机制增强TSA诱导的胃癌细胞凋亡

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Aims: To analyze the combined impact of the histone deacetylase inhibitor (HDACI) Trichostatin A (TSA) and the extracellular-signal-regulated kinase 1/2 (ERK1/2) inhibitor PD98059 on gastric cancer (GC) cell line SGC7901 growth. Main methods: SGC7901 cells were treated with TSA, PD98059 or with a TSA-PD98059 combination. Effects of drug treatment on tumor cell proliferation, apoptosis, cell cycle progression, and cell signaling pathways were investigated by MTS assay, flow cytometry, Western blotting, chromatin immunoprecipitation (ChIP) assay, electrophoretic mobility shift assay (EMSA), and luciferase reporter assay, respectively. Key findings: PD98059 enhanced TSA-induced cell growth arrest, apoptosis and activation of p21 WAF1/CIP1, but reversed TSA-induced activation of ERK1/2 and nuclear factor-κB (NF-κB). TSA alone up-regulated Notch1 and Hes1, and down-regulated Notch2, but PD98059 did not affect the trends of Notch1 and Notch2 induced by TSA. Particularly, PD98059 did potentiate the ability of TSA to down-regulate phospho-histone H3 protein, but increased levels of the acetylated forms of histone H3 bound to the p21 WAF1/CIP1 promoter, leading to enhanced expression of p21 WAF1/CIP1 in SGC7901 cells. Significance: PD98059 synergistically potentiates TSA-induced GC growth arrest and apoptosis by manipulating NF-κB and p21 WAF1/CIP1 independent of Notch. Therefore, concomitant administration of HDACIs and ERK1/2 inhibitors may be a promising treatment strategy for individuals with GC.
机译：目的：分析组蛋白脱乙酰基酶抑制剂（HDACI）曲古抑菌素A（TSA）和细胞外信号调节激酶1/2（ERK1 / 2）抑制剂PD98059对胃癌细胞（GC）SGC7901生长的综合影响。主要方法：将SGC7901细胞用TSA，PD98059或TSA-PD98059组合处理。通过MTS分析，流式细胞仪，Western印迹，染色质免疫沉淀（ChIP）分析，电泳迁移率变动分析（EMSA）和荧光素酶报告基因分析研究了药物治疗对肿瘤细胞增殖，凋亡，细胞周期进程和细胞信号通路的影响。 ， 分别。关键发现：PD98059增强了TSA诱导的细胞生长停滞，凋亡和p21 WAF1 / CIP1的激活，但逆转了TSA诱导的ERK1 / 2和核因子-κB（NF-κB）的激活。 TSA单独上调Notch1和Hes1，下调Notch2，但PD98059不会影响TSA诱导的Notch1和Notch2的趋势。特别地，PD98059确实增强了TSA下调磷酸组蛋白H3蛋白的能力，但增加了与p21 WAF1 / CIP1启动子结合的组蛋白H3乙酰化形式的水平，导致p21 WAF1 / CIP1在SGC7901细胞中的表达增强。意义：PD98059通过操纵独立于Notch的NF-κB和p21 WAF1 / CIP1协同增强TSA诱导的GC生长停滞和细胞凋亡。因此，HDACI和ERK1 / 2抑制剂的同时给药可能是GC患者的一种有前途的治疗策略。

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