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

doi:10.1016/j.omto.2022.08.004

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

Mol Ther Oncolytics. 2022 Aug 5:26:387-398. doi: 10.1016/j.omto.2022.08.004. eCollection 2022 Sep 15.

Authors

Po-Ming Chow^{1

2}, Jun-Ren Dong^{1

2}, Yu-Wei Chang^{1

2

3}, Kuan-Lin Kuo^{1

2

4}, Wei-Chou Lin⁵, Shing-Hwa Liu^{4

6

7}, Kuo-How Huang^{1

2}

Affiliations

¹ Department of Urology, National Taiwan University Hospital, Taipei 100, Taiwan.
² Department of Urology, College of Medicine, National Taiwan University, Taipei 100, Taiwan.
³ Department of Biomedical Sciences, Cornell University, Ithaca, NY 14853, USA.
⁴ Graduate Institute of Toxicology, College of Medicine, National Taiwan University, Taipei 100, Taiwan.
⁵ Department of Pathology, National Taiwan University Hospital, Taipei 100, Taiwan.
⁶ Department of Medical Research, China Medical University Hospital, China Medical University, Taichung 404, Taiwan.
⁷ Department of Pediatrics, National Taiwan University Hospital, Taipei 100, Taiwan.

Abstract

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.

Keywords: ER stress; bladder cancer; cancer stem cell; chemoresistance; deubiquitination.