Dai Huiqi, Wang Guoli, Cao Wenmin, Qi Wei, Chen Wei, Guo Hongqian
Department of Urology, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210008, P.R. China.
Department of Urology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Institute of Urology Nanjing University, Nanjing, Jiangsu 210008, P.R. China.
Oncol Lett. 2023 May 10;25(6):274. doi: 10.3892/ol.2023.13860. eCollection 2023 Jun.
Most patients with renal cancer will develop resistance to sorafenib therapy and will therefore exhibit disease progression. Effective therapies for these patients are extremely limited. Cyclooxygenase-2 (COX-2) promotes the malignant transformation of cancer cells and drug resistance. The potential of COX-2 inhibitor (celecoxib) administration in combination with sorafenib for the treatment of renal cancer is unclear. The present study demonstrated that sorafenib rapidly increased the expression of COX-2 in renal cancer cells, as determined using reverse transcription-quantitative PCR and western blotting. The results of the MTT assay and cell apoptosis experiment demonstrated that the cytotoxicity of sorafenib was also affected by COX-2 expression and celecoxib enhanced the cytotoxicity of sorafenib against renal cell carcinoma. Immunofluorescence analysis indicated that sorafenib induced the formation of stress granules (SGs) in renal cancer cells. In addition, COX-2 expression was associated with the formation of SGs, and SGs could capture and stabilize COX-2 mRNAs in renal cancer cells; this was confirmed using RNA fluorescence hybridization and an actinomycin D chase experiment. The protective effect of SGs was further demonstrated in cell experiments and xenograft tumor models. Thus, the present study indicated that the use of celecoxib may significantly enhance the sensitivity of renal cancer cells to sorafenib and improve efficacy. Sorafenib-induced SGs may contribute to critical events that promote COX-2 expression and survival in renal cancer cells. Therefore, the present study may provide novel ideas for the treatment of renal cancer.
大多数肾癌患者会对索拉非尼治疗产生耐药性，因此会出现疾病进展。针对这些患者的有效治疗方法极为有限。环氧化酶-2（COX-2）促进癌细胞的恶性转化和耐药性。COX-2抑制剂（塞来昔布）联合索拉非尼治疗肾癌的潜力尚不清楚。本研究表明，使用逆转录定量PCR和蛋白质印迹法测定，索拉非尼可迅速增加肾癌细胞中COX-2的表达。MTT试验和细胞凋亡实验结果表明，索拉非尼的细胞毒性也受COX-2表达的影响，塞来昔布可增强索拉非尼对肾细胞癌的细胞毒性。免疫荧光分析表明，索拉非尼可诱导肾癌细胞中应激颗粒（SGs）的形成。此外，COX-2表达与SGs的形成相关，SGs可捕获并稳定肾癌细胞中的COX-2 mRNA；这通过RNA荧光杂交和放线菌素D追踪实验得到证实。在细胞实验和异种移植肿瘤模型中进一步证明了SGs的保护作用。因此，本研究表明，使用塞来昔布可能会显著提高肾癌细胞对索拉非尼的敏感性并提高疗效。索拉非尼诱导的SGs可能促成促进肾癌细胞中COX-2表达和存活的关键事件。因此，本研究可能为肾癌治疗提供新思路。
