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

Urothelial carcinoma (UC) comprises nearly all bladder cancers. Standard platinum-based chemotherapy includes a response rate of roughly 50%, but drug resistance develops after short-term treatment. Deubiquitinating (DUB) enzyme inhibitors increase protein polyubiquitination and endoplasmic reticulum (ER) stress, that 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 says b-AP15 caused ER stress and apoptosis in BFTC905, T24, T24/R (cisplatin-resistant), and RT4 urothelial carcinoma cell lines. Inhibition from the MYC signaling path and cancer stemness by b-AP15 was confirmed by RNA sequencing, RT-PCR, immunoblotting, and sphere-developing assays. Within the mouse xenograft model, the mixture of b-AP15 and cisplatin demonstrated superior therapeutic effects in contrast to either monotherapy.