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TRPV1 Antagonist DWP05195 Induces ER Stress-Dependent Apoptosis through the ROS-p38-CHOP Pathway in Human Ovarian Cancer Cells

1
Department of Life and Nanopharmaceutical Sciences, Kyung Hee University, Seoul 02447, Korea
2
College of Pharmacy, Kyung Hee University, Seoul 02447, Korea
3
Division of Tumor Immunology, Center for Gynecologic Cancer & Center for Clinical Trials, National Cancer Center, Goyang 10408, Korea
*
Author to whom correspondence should be addressed.
Cancers 2020, 12(6), 1702; https://doi.org/10.3390/cancers12061702
Received: 22 May 2020 / Revised: 19 June 2020 / Accepted: 24 June 2020 / Published: 26 June 2020
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. View Full-Text
Keywords: DWP05195; TRPV1 antagonist; ovarian cancer; ER stress; CHOP; ROS DWP05195; TRPV1 antagonist; ovarian cancer; ER stress; CHOP; ROS
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Wang, Y.-Y.; Lee, K.-T.; Lim, M.C.; Choi, J.-H. TRPV1 Antagonist DWP05195 Induces ER Stress-Dependent Apoptosis through the ROS-p38-CHOP Pathway in Human Ovarian Cancer Cells. Cancers 2020, 12, 1702.

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