Katari Venkatesh, Dalal Kesha, Kondapalli Narendra, Paruchuri Sailaja, Nadiminty Nagalakshmi, Thodeti Charles K
Department of Physiology and Pharmacology, College of Medicine and Lifesciences, The University of Toledo, Toledo, Ohio.
Department of Urology, College of Medicine and Lifesciences, The University of Toledo, Toledo, Ohio.
J Pharmacol Exp Ther. 2025 Jul 22;392(9):103665. doi: 10.1016/j.jpet.2025.103665.
Bladder cancer (BLCA) is the second most common urologic cancer in the United States and worldwide and mostly affects the aging population. Despite several ongoing clinical trials, treatment paradigms for BLCA have not changed significantly. Here, we investigated the expression of transient receptor potential vanilloid type 4 (TRPV4) in patients with BLCA and its role in calcium influx, cell proliferation, and migration using normal human urothelial cells and BLCA cells. Bioinformatic analysis of the University of Alabama at Birmingham Cancer Data Analysis Portal and cBioPortal databases revealed that TRPV4 expression is significantly higher in human BLCA tissues than in normal adjacent tissues. Furthermore, TRPV4 expression was markedly elevated in early-stage BLCA and upregulated in muscle-invasive bladder cancer tissues. TRPV4 is expressed in both normal urothelial (SV-HUC-1) and BLCA (T-24) cells, and functional assays demonstrated enhanced TRPV4-mediated calcium influx in T-24 compared with SV-HUC-1 cells. T-24 cells exhibited higher spreading on extracellular matrix gels with increasing stiffness (0.2, 8, and 50 kPa) and exhibited a migratory phenotype compared to SV-HUC-1 cells. Pharmacological inhibition of TRPV4 significantly reduced proliferation and migration in T-24 cells but had minimal effects on normal cells. Finally, treatment with cisplatin significantly reduced TRPV4 protein levels and TRPV4-mediated calcium influx in chemosensitive UM-UC-3 cells but remained unchanged in chemoresistant T-24 cells, suggesting a potential role of TRPV4 in chemoresistance. In conclusion, TRPV4 may contribute to BLCA progression by regulating cell proliferation and migration and may impart resistance to chemotherapy. Targeting TRPV4 could present a novel therapeutic approach for managing BLCA progression and overcoming chemoresistance. SIGNIFICANCE STATEMENT: This study identified transient receptor potential vanilloid type 4 (TRPV4) as a critical driver of bladder cancer (BLCA) progression. TRPV4 gene expression is elevated in both early-stage and muscle-invasive BLCA tissues. Importantly, TRPV4 inhibition selectively reduces BLCA growth and motility. Furthermore, TRPV4 is downregulated by cisplatin in chemosensitive but not chemoresistant BLCA cells, underscoring its key role in bladder cancer chemoresistance. These findings position TRPV4 as a therapeutic target for enhancing BLCA treatment and overcoming drug resistance.
膀胱癌（BLCA）是美国和全球第二常见的泌尿系统癌症，主要影响老年人群。尽管有多项临床试验正在进行，但BLCA的治疗模式并未发生显著变化。在此，我们使用正常人膀胱上皮细胞和BLCA细胞，研究了瞬时受体电位香草酸亚型4（TRPV4）在BLCA患者中的表达及其在钙内流、细胞增殖和迁移中的作用。对阿拉巴马大学伯明翰分校癌症数据分析门户和cBioPortal数据库的生物信息学分析显示，人BLCA组织中TRPV4的表达显著高于相邻正常组织。此外，TRPV4在早期BLCA中表达明显升高，在肌层浸润性膀胱癌组织中上调。TRPV4在正常膀胱上皮（SV-HUC-1）细胞和BLCA（T-24）细胞中均有表达，功能试验表明，与SV-HUC-1细胞相比，T-24细胞中TRPV4介导的钙内流增强。随着细胞外基质凝胶硬度增加（0.2、8和50 kPa），T-24细胞在其表面的铺展能力增强，且与SV-HUC-1细胞相比呈现出迁移表型。TRPV4的药理学抑制显著降低了T-24细胞的增殖和迁移，但对正常细胞影响极小。最后，顺铂处理显著降低了化疗敏感的UM-UC-3细胞中TRPV4蛋白水平和TRPV4介导的钙内流，但在化疗耐药的T-24细胞中保持不变，这表明TRPV4在化疗耐药中可能发挥作用。总之，TRPV4可能通过调节细胞增殖和迁移促进BLCA进展，并可能赋予化疗耐药性。靶向TRPV4可能为控制BLCA进展和克服化疗耐药性提供一种新治疗方法。意义声明：本研究确定瞬时受体电位香草酸亚型4（TRPV4）是膀胱癌（BLCA）进展的关键驱动因素。TRPV4基因表达在早期和肌层浸润性BLCA组织中均升高。重要的是，TRPV4抑制选择性地降低了BLCA的生长和运动能力。此外，顺铂在化疗敏感而非化疗耐药的BLCA细胞中下调TRPV4，突出了其在膀胱癌化疗耐药中的关键作用。这些发现使TRPV4成为增强BLCA治疗和克服耐药性的治疗靶点。
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