TRPV1 Antagonist DWP05195 Induces ER Stress-Dependent Apoptosis through the ROS-p38-CHOP Pathway in Human Ovarian Cancer Cells
TRPV1 Antagonist DWP05195 Induces ER Stress-Dependent Apoptosis through the ROS-p38-CHOP Pathway in Human Ovarian Cancer Cells
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DOI：
10.3390/cancers12061702
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发表时间：
2020-06-01
期刊：
影响因子：
5.2
通讯作者：
Choi, Jung-Hye
中科院分区：
文献类型：
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作者：
Wang, Yi-Yue;Lee, Kyung-Tae;Choi, Jung-Hye
除了它们的镇痛活性外，瞬时受体潜力香草素1(TRPV1)激动剂和拮抗剂在各种人类癌症中都显示出深刻的抗癌活性。在本研究中，我们研究了一种新的TRPV1拮抗剂DWP05195的抗癌活性，并探讨了其在人卵巢癌细胞中的分子机制。DWP05195对所检测的五种卵巢癌细胞株均显示出明显的生长抑制作用。DWP05195通过激活caspase-3、-8和-9诱导细胞凋亡。DWP05195诱导C/EBP同源蛋白(CHOP)表达和内质网(ER)应激。内质网应激抑制剂苯丁酸钠(4-PBA)和CHOP基因敲除显著抑制DWP5195诱导的细胞死亡。DWP05195增强的CHOP表达通过调节Bcl2样蛋白11(BIM)、死亡受体4(DR4)和DR5刺激内源性和外源性的凋亡通路。DWP05195诱导的细胞死亡与活性氧(ROS)水平升高和p38通路激活有关。抗氧化剂N-乙酰-L-半胱氨酸(NAC)可显著抑制DWP05195诱导的CHOP表达和p38激活。通过p47Phox基因敲除抑制NADPH氧化酶(NOx)可阻断DWP05195诱导的CHOP表达和细胞死亡。综上所述，研究结果表明，DWP05195通过ROS-p38-CHOP通路诱导人卵巢癌细胞内质网应激诱导细胞凋亡。
In addition to their analgesic activity, transient receptor potential vanilloid 1 (TRPV1) agonists and antagonists demonstrate profound anti-cancer activities in various human cancers. In the present study, we investigated the anti-cancer activity of a novel TRPV1 antagonist, DWP05195, and evaluated its molecular mechanism in human ovarian cancer cells. DWP05195 demonstrated potent growth inhibitory effects in all five ovarian cancer cell lines examined. DWP05195 induced apoptosis through the activation of caspase-3, -8, and -9. DWP05195 induced C/EBP homologous protein (CHOP) expression and endoplasmic reticulum (ER) stress. Sodium phenylbutyrate (4-PBA), an ER-stress inhibitor, and CHOP knockdown significantly suppressed DWP5195-induced cell death. DWP05195-enhanced CHOP expression stimulated intrinsic and extrinsic apoptotic pathways through the regulation of Bcl2-like11 (BIM), death receptor 4 (DR4), and DR5. DWP05195-induced cell death was associated with increased reactive oxygen species (ROS) levels and p38 pathway activation. Pre-treatment with the antioxidant N-acetyl-L-cysteine (NAC) significantly suppressed DWP05195-induced CHOP expression and p38 activation. Inhibition of NADPH oxidase (NOX) through p47phox knockdown abolished DWP05195-induced CHOP expression and cell death. Taken together, the findings indicate that DWP05195 induces ER stress-induced apoptosis via the ROS-p38-CHOP pathway in human ovarian cancer cells.