Ye Yixian, Wang Peng, Wu Daquan, Tang Fengrong, Shen Na, Hou Guanghui
Department of Otorhinolaryngology, Zhongshan Hospital, Fudan University (Xiamen Branch), Xiamen City, Fujian Province.
Department of Otorhinolaryngology-Head and Neck Surgery, Zhongshan Hospital, Fudan University, Shanghai City.
Anticancer Drugs. 2025 Aug 1;36(7):539-548. doi: 10.1097/CAD.0000000000001721. Epub 2025 Apr 23.
The overexpression of CAV1 in many cancers is linked to chemotherapy resistance, but the exact mechanisms by which CAV1 contributes to resistance in nasopharyngeal carcinoma (NPC) are not fully known. Our research aims to elucidate the potential pathways by which CAV1 contributes to chemotherapy resistance in NPC, providing a basis for developing strategies to overcome resistance. A docetaxel-resistant NPC cell line was established, and CAV1 expression was analyzed in the cell line and the resistant variant using western blot. The sensitivity of the resistant cell line to docetaxel was assessed via cell counting kit-8, colony formation assays, and flow cytometry. Flow cytometry was used to measure lipid reactive oxygen species levels, while kits were employed to determine Fe 2+ and malondialdehyde concentrations. The Ubibrowser database helped identify ubiquitination enzymes that interact with CAV1. The binding relationship between UCHL1 and CAV1 was studied using co-immunoprecipitation and immunofluorescence, which also evaluated the deubiquitination activity of UCHL1 on CAV1. CAV1 is overexpressed in NPC tissues and cells, correlating with adverse patient prognoses. In docetaxel-resistant cells, CAV1 expression is elevated compared to standard NPC cells. Silencing CAV1 increased the sensitivity of these resistant cells to docetaxel. Additionally, treatment with the ferroptosis inducer erastin could counteract the effects of CAV1 overexpression on drug resistance. UCHL1 interacted with CAV1 and inhibited its ubiquitin-mediated degradation pathway. By deubiquitinating CAV1, UCHL1 stabilizes and increases its expression, which inhibits ferroptosis and enhances the resistance of NPC cells to docetaxel.
CAV1在许多癌症中的过表达与化疗耐药性相关，但CAV1导致鼻咽癌（NPC）耐药的确切机制尚不完全清楚。我们的研究旨在阐明CAV1导致NPC化疗耐药的潜在途径，为制定克服耐药性的策略提供依据。建立了多西他赛耐药的NPC细胞系，并通过蛋白质免疫印迹法分析该细胞系和耐药变体中CAV1的表达。通过细胞计数试剂盒-8、集落形成试验和流式细胞术评估耐药细胞系对多西他赛的敏感性。流式细胞术用于测量脂质活性氧水平，试剂盒用于测定Fe2+和丙二醛浓度。Ubibrowser数据库帮助识别与CAV1相互作用的泛素化酶。使用免疫共沉淀和免疫荧光研究UCHL1与CAV1之间的结合关系，同时也评估UCHL1对CAV1的去泛素化活性。CAV1在NPC组织和细胞中过表达，与患者不良预后相关。在多西他赛耐药细胞中，CAV1的表达相对于标准NPC细胞有所升高。沉默CAV1可增加这些耐药细胞对多西他赛的敏感性。此外，用铁死亡诱导剂erastin处理可抵消CAV1过表达对耐药性的影响。UCHL1与CAV1相互作用并抑制其泛素介导的降解途径。通过使CAV1去泛素化，UCHL1使其稳定并增加其表达，从而抑制铁死亡并增强NPC细胞对多西他赛的耐药性。
