The UCHL5 inhibitor b-AP15 overcomes cisplatin resistance via suppression of cancer stemness in urothelial carcinoma

Po-Ming Chow; Jun-Ren Dong; Yu-Wei Chang; Kuan-Lin Kuo; Wei-Chou Lin; Shing-Hwa Liu; Kuo-How Huang

Molecular Therapy: Oncolytics (Sep 2022)

The UCHL5 inhibitor b-AP15 overcomes cisplatin resistance via suppression of cancer stemness in urothelial carcinoma

Po-Ming Chow,
Jun-Ren Dong,
Yu-Wei Chang,
Kuan-Lin Kuo,
Wei-Chou Lin,
Shing-Hwa Liu,
Kuo-How Huang

Affiliations

Po-Ming Chow: Department of Urology, National Taiwan University Hospital, Taipei 100, Taiwan; Department of Urology, College of Medicine, National Taiwan University, Taipei 100, Taiwan
Jun-Ren Dong: Department of Urology, National Taiwan University Hospital, Taipei 100, Taiwan; Department of Urology, College of Medicine, National Taiwan University, Taipei 100, Taiwan
Yu-Wei Chang: Department of Urology, National Taiwan University Hospital, Taipei 100, Taiwan; Department of Urology, College of Medicine, National Taiwan University, Taipei 100, Taiwan; Department of Biomedical Sciences, Cornell University, Ithaca, NY 14853, USA
Kuan-Lin Kuo: Department of Urology, National Taiwan University Hospital, Taipei 100, Taiwan; Department of Urology, College of Medicine, National Taiwan University, Taipei 100, Taiwan; Graduate Institute of Toxicology, College of Medicine, National Taiwan University, Taipei 100, Taiwan
Wei-Chou Lin: Department of Pathology, National Taiwan University Hospital, Taipei 100, Taiwan
Shing-Hwa Liu: Graduate Institute of Toxicology, College of Medicine, National Taiwan University, Taipei 100, Taiwan; Department of Medical Research, China Medical University Hospital, China Medical University, Taichung 404, Taiwan; Department of Pediatrics, National Taiwan University Hospital, Taipei 100, Taiwan
Kuo-How Huang: Department of Urology, National Taiwan University Hospital, Taipei 100, Taiwan; Department of Urology, College of Medicine, National Taiwan University, Taipei 100, Taiwan; Corresponding author Kuo-How Huang, MD, PhD, Department of Urology, National Taiwan University Hospital and College of Medicine, National Taiwan University, No. 7, Zhongshan S. Rd., Zhongzheng Dist., Taipei 100, Taiwan.

Journal volume & issue: Vol. 26
pp. 387 – 398

Abstract

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Urothelial carcinoma (UC) comprises the majority of bladder cancers. Standard platinum-based chemotherapy has a response rate of approximately 50%, but drug resistance develops after short-term treatment. Deubiquitinating (DUB) enzyme inhibitors increase protein polyubiquitination and endoplasmic reticulum (ER) stress, which might further suppress cancer stemness and overcome cisplatin resistance. Therefore, we investigated the cytotoxic effect and potential mechanisms of b-AP15 on urothelial carcinoma. Our results revealed that b-AP15 induced ER stress and apoptosis in BFTC905, T24, T24/R (cisplatin-resistant), and RT4 urothelial carcinoma cell lines. Inhibition of the MYC signaling pathway and cancer stemness by b-AP15 was confirmed by RNA sequencing, RT-PCR, immunoblotting, and sphere-forming assays. In the mouse xenograft model, the combination of b-AP15 and cisplatin showed superior therapeutic effects compared with either monotherapy.

Published in Molecular Therapy: Oncolytics

ISSN: 2372-7705 (Online)
Publisher: Elsevier
Country of publisher: United Kingdom
LCC subjects: Medicine: Internal medicine: Neoplasms. Tumors. Oncology. Including cancer and carcinogens
Website: http://www.cell.com/molecular-therapy-family/oncolytics/latest-content

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