The involvement of Bcl-2 family proteins in AKT-regulated cell survival in cisplatin resistant epithelial ovarian cancer.
The involvement of Bcl-2 family proteins in AKT-regulated cell survival in cisplatin resistant epithelial ovarian cancer.
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DOI：
10.18632/oncotarget.13817
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发表时间：
2017-01-03
期刊：
影响因子：
--
通讯作者：
Wang D
中科院分区：
文献类型：
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作者：
Dai Y;Jin S;Li X;Wang D
许多涉及顺铂耐药卵巢癌患者的研究表明，AKT激活导致细胞凋亡抑制。本研究的目的是检查Bcl-2家族蛋白在顺铂治疗后AKT调节的细胞存活中的潜在参与。顺铂敏感（PEO 1）和顺铂耐药（PEO 4）细胞取自卵巢癌患者顺铂治疗前和化疗耐药后的腹水。结果发现，顺铂处理激活AKT信号通路，促进顺铂耐药EOC细胞的细胞增殖。当AKT转染到顺铂耐药卵巢癌细胞的细胞核中时，DNA-PK在S473处磷酸化。这些细胞中激活的AKT（pAKT-S473）抑制顺铂诱导的死亡信号，从而抑制顺铂介导的凋亡。本研究的结果表明，顺铂、DNA-PK抑制剂NU 7441和AKT抑制剂TCN的组合可以克服耐药性，增加凋亡，并使PEO 4细胞对顺铂治疗重新敏感。当Bad被siRNA下调时，在PEO 4细胞中观察到凋亡活性降低，这表明Bad促进PEO 4细胞的凋亡。Bcl-2抑制剂ABT-737的使用表明，ABT-737结合Bcl-2，但不结合Mcl-1，并释放Bax/巴克，导致细胞凋亡。ABT-737和顺铂的组合导致PEO 1和PEO 4细胞死亡的显著增加。总之，这些结果表明Bcl-2家族蛋白是耐药性的调节剂。联合应用顺铂和Bcl-2家族蛋白抑制剂可能成为治疗顺铂耐药卵巢癌的一种策略。
Many studies involving patients with cisplatin-resistant ovarian cancer have shown that AKT activation leads to inhibition of apoptosis. The aim of this study was to examine the potential involvement of the Bcl-2 family proteins in AKT-regulated cell survival in response to cisplatin treatment. Cisplatin-sensitive (PEO1) and cisplatin-resistant (PEO4) cells were taken from ascites of patients with ovarian cancer before cisplatin treatment and after development of chemoresistance. It was found that cisplatin treatment activated the AKT signaling pathway and promoted cell proliferation in cisplatin-resistant EOC cells. When AKT was transfected into nucleus of cisplatin-resistant ovarian cancer cells, DNA-PK was phosphorylated at S473. The activated AKT (pAKT-S473) in these cells inhibited the death signal induced by cisplatin thereby inhibiting cisplatin-mediated apoptosis. Results from this study showed that the combination of cisplatin, DNA-PK inhibitor NU7441, and AKT inhibitor TCN can overcome drug resistance, increase apoptosis, and re-sensitize PEO4 cells to cisplatin treatment. A decrease in apoptotic activity was seen in PEO4 cells when Bad was downregulated by siRNA, which indicated that Bad promotes apoptosis in PEO4 cells. Use of the Bcl-2 inhibitor ABT-737 showed that ABT-737 binds to Bcl-2 but not Mcl-1 and releases Bax/Bak which leads to cell apoptosis. The combination of ABT-737 and cisplatin leads to a significant increase in the death of PEO1 and PEO4 cells. All together, these results indicate that Bcl-2 family proteins are regulators of drug resistance. The combination of cisplatin and Bcl-2 family protein inhibitor could be a strategy for the treatment of cisplatin-resistant ovarian cancer.