泛素羧基末端水解酶L5抑制剂b-AP15通过抑制尿路上皮癌的肿瘤干性克服顺铂耐药性。
The UCHL5 inhibitor b-AP15 overcomes cisplatin resistance via suppression of cancer stemness in urothelial carcinoma.
作者信息
Chow Po-Ming, Dong Jun-Ren, Chang Yu-Wei, Kuo Kuan-Lin, Lin Wei-Chou, Liu Shing-Hwa, Huang Kuo-How
机构信息
Department of Urology, National Taiwan University Hospital, Taipei 100, Taiwan.
Department of Urology, College of Medicine, National Taiwan University, Taipei 100, Taiwan.
出版信息
Mol Ther Oncolytics. 2022 Aug 5;26:387-398. doi: 10.1016/j.omto.2022.08.004. eCollection 2022 Sep 15.
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.
尿路上皮癌（UC）占膀胱癌的大多数。标准的铂类化疗的缓解率约为50%，但短期治疗后会产生耐药性。去泛素化（DUB）酶抑制剂可增加蛋白质多聚泛素化和内质网（ER）应激，这可能进一步抑制癌症干性并克服顺铂耐药性。因此，我们研究了b-AP15对尿路上皮癌的细胞毒性作用及其潜在机制。我们的结果显示，b-AP15在BFTC905、T24、T24/R（顺铂耐药）和RT4尿路上皮癌细胞系中诱导ER应激和细胞凋亡。通过RNA测序、RT-PCR、免疫印迹和球形成试验证实了b-AP15对MYC信号通路和癌症干性的抑制作用。在小鼠异种移植模型中，与单一疗法相比，b-AP15和顺铂联合使用显示出更好的治疗效果。
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