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Upregulation of DR5 and Downregulation of Survivin by IITZ-01, Lysosomotropic Autophagy Inhibitor, Potentiates TRAIL-Mediated Apoptosis in Renal Cancer Cells via Ubiquitin-Proteasome Pathway

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Author(s)
Sk Abrar ShahriyarSeung Un SeoKyoung-Jin MinPeter KubatkaDo Sik MinJong-Soo ChangDong Eun KimSeon Min WooTaeg Kyu Kwon
Keimyung Author(s)
Kim, Dong EunKwon, Taeg Kyu
Department
Dept. of Otorhinolaryngology (이비인후과학)
Dept. of Immunology (면역학)
Journal Title
Cancers
Issued Date
2020
Volume
12
Issue
9
Keyword
IITZ-01TRAILDR5survivinUSP9X
Abstract
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) selectively is able to increase apoptosis in cancer cells as agent with minimum toxicity to noncancerous cells. However, all cancer cells are not sensitive to TRAIL-induced apoptosis. In this study, we showed the sub-lethal concentrations of a lysosomotropic autophagy inhibitor, IITZ-01, sensitizes cancer cells (renal, lung, and breast carcinoma) to TRAIL-induced apoptosis through DR5 upregulation and survivin downregulation through ubiquitin-proteasome pathway. Knockdown of DR5 or overexpression of survivin inhibited combined treatment with IITZ-01 and TRAIL-induced apoptosis. IITZ-01 downregulated protein expression of Cbl, ubiquitin E3 ligase, and decreased expression level of Cbl markedly led to increase DR5 protein expression and TRAIL sensitivity. Moreover, IITZ-01 decreased expression level of survivin protein via downregulation of deubiquitinase ubiquitin-specific protease 9X (USP9X) expression. Taken together, these results provide the first evidence that IITZ-01 enhances TRAIL-mediated apoptosis through DR5 stabilization by downregulation of Cbl and USP9X-dependent survivin ubiquitination and degradation in renal carcinoma cells.
Keimyung Author(s)(Kor)
김동은
권택규
Publisher
School of Medicine (의과대학)
Citation
Sk Abrar Shahriyar et al. (2020). Upregulation of DR5 and Downregulation of Survivin by IITZ-01, Lysosomotropic Autophagy Inhibitor, Potentiates TRAIL-Mediated Apoptosis in Renal Cancer Cells via Ubiquitin-Proteasome Pathway. Cancers, 12(9), 2363–2377. doi: 10.3390/cancers12092363
Type
Article
ISSN
2072-6694
Source
https://www.mdpi.com/2072-6694/12/9/2363
DOI
10.3390/cancers12092363
URI
https://kumel.medlib.dsmc.or.kr/handle/2015.oak/43005
Appears in Collections:
1. School of Medicine (의과대학) > Dept. of Immunology (면역학)
1. School of Medicine (의과대학) > Dept. of Otorhinolaryngology (이비인후과학)
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