Hsp90 Inhibitor SNX-2112 Enhances TRAIL-Induced Apoptosis of Human Cervical Cancer Cells via the ROS-Mediated JNK-p53-Autophagy-DR5 Pathway
Hsp90 Inhibitor SNX-2112 Enhances TRAIL-Induced Apoptosis of Human Cervical Cancer Cells via the ROS-Mediated JNK-p53-Autophagy-DR5 Pathway
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DOI：
10.1155/2019/9675450
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发表时间：
2019-01-01
影响因子：
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通讯作者：
Liu, Zhong
中科院分区：
文献类型：
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作者：
Hu, Liubing;Wang, Yan;Liu, Zhong
肿瘤坏死因子相关凋亡诱导配体（tumor necrosis factor-related apoptosis-inducing ligand，TRAIL）是一种有效的肿瘤细胞凋亡诱导因子，可诱导多种肿瘤细胞凋亡。然而，癌细胞对TRAIL的耐药性是创造有效的TRAIL靶向临床疗法的巨大障碍。因此，需要能够增强TRAIL的作用或克服其抗性的试剂。本研究将TRAIL与SNX-2112联合应用，探讨SNX-2112增强TRAIL诱导宫颈癌细胞凋亡的作用及其机制。我们的研究结果表明，SNX-2112显着增强TRAIL诱导的细胞毒性在HeLa细胞，这种组合被认为是协同作用。此外，我们发现SNX-2112在TRAIL耐药的HeLa细胞中敏化TRAIL介导的凋亡半胱天冬酶依赖性。SNX-2112下调抗凋亡蛋白，包括Bcl-2，Bcl-XL和FLIP，促进活性氧（ROS）的积累，并增加p-JNK和p53的表达水平。ROS清除剂NAC拯救SNX-2112/TRAIL诱导的细胞凋亡，并抑制SNX-21 I2诱导的p-JNK和p53。此外，SNX-21 I2诱导HeLa细胞中死亡受体DR 5的上调。通过siRNA沉默DR 5显著减少SNX-2112和TRAIL的联合作用引起的细胞凋亡。此外，SNX-2112抑制Akt/mTOR信号通路并诱导HeLa细胞中的自噬。巴弗洛霉素A1或Atg 7 siRNA对自噬的阻断消除了SNX-2112诱导的DR 5上调。同时，使用ROS清除剂NAC、JNK抑制剂SP 600125和p53抑制剂PFT α来验证自噬介导的DR 5上调是由SNX-2112刺激的ROS-JNK-p53信号通路的激活调节的。因此，SNX-21 I2和TRAIL的组合可能通过克服细胞凋亡抗性的细胞机制为治疗人宫颈癌提供新的策略。
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a potent cancer cell apoptosis-inducing factor that can induce apoptosis in a variety of cancer cells. However, resistance to TRAIL in cancer cells is a huge obstacle in creating effective TRAIL-targeted clinical therapies. Thus, agents that can either enhance the effect of TRAIL or overcome its resistance are needed. In this study, we combined TRAIL with SNX-2112, an Hsp90 inhibitor we previously developed, to explore the effect and mechanism that SNX-2112 enhanced TRAIL-induced apoptosis in cervical cancer cells. Our results showed that SNX-2112 markedly enhanced TRAIL-induced cytotoxicity in HeLa cells, and this combination was found to be synergistic. Additionally, we found that SNX-2112 sensitized TRAIL-mediated apoptosis caspase-dependently in TRAIL-resistant HeLa cells. Mechanismly, SNX-2112 downregulated antiapoptosis proteins, including Bcl-2, Bcl-XL, and FLIP, promoted the accumulation of reactive oxygen species (ROS), and increased the expression levels of p-JNK and p53. ROS scavenger NAC rescued SNX-2112/TRAIL-induced apoptosis and suppressed SNX-21I2-induced p-JNK and p53. Moreover, SNX-21I2 induced the upregulation of death-receptor DR5 in HeLa cells. The silencing of DR5 by siRNA significantly decreased cell apoptosis by the combined effect of SNX-2112 and TRAIL. In addition, SNX-2112 inhibited the Akt/mTOR signaling pathway and induced autophagy in HeLa cells. The blockage of autophagy by bafilomycin Al or Atg7 siRNA abolished SNX-2112-induced upregulation of DR5. Meanwhile, ROS scavenger NAC, JNK inhibitor SP600125, and p53 inhibitor PFT alpha were used to verify that autophagy-mediated upregulation of DR5 was regulated by the SNX-2112-stimulated activation of the ROS-JNK-p53 signaling pathway. Thus, the combination of SNX-21I2 and TRAIL may provide a novel strategy for the treatment of human cervical cancer by overcoming cellular mechanisms of apoptosis resistance.