Department of Urology, Tongren Hospital Shanghai Jiao Tong University School of Medicine, Shanghai 200336, China.
College of Medicine, Yanbian University, Yanji 133002, China.
Cell Signal. 2024 Dec;124:111421. doi: 10.1016/j.cellsig.2024.111421. Epub 2024 Sep 17.
Sunitinib resistance presents a significant challenge in the treatment of clear cell renal cell carcinoma (ccRCC). The role of TRIB3, a newly identified oncogene, in tumor drug resistance has been widely studied. However, the mechanism by which TRIB3 contributes to sunitinib resistance in ccRCC has not been previously explored. This study aimed to investigate the mechanism through which TRIB3 regulates ferroptosis to increase the susceptibility of ccRCC to sunitinib treatment. Bioinformatics analysis and experimental validation revealed that TRIB3 is significantly upregulated in ccRCC tissues and is associated with poor prognosis. Knockdown of TRIB3 using siRNA transfection inhibited the proliferation and migration of ccRCC cells and induced ferroptosis. Following sunitinib treatment, TRIB3 knockdown increased cell sensitivity to sunitinib, enhanced the suppressive impact of sunitinib, and augmented sunitinib-induced ferroptosis. This study demonstrated that TRIB3 knockdown induces ferroptosis by targeting the SLC7A11/GPX4 pathway and enhances therapeutic efficacy of sunitinib for ccRCC, providing new insights and potential strategies to overcome the challenge of sunitinib resistance in ccRCC.
舒尼替尼耐药是治疗肾透明细胞癌（ccRCC）的重大挑战。新鉴定的癌基因 TRIB3 在肿瘤药物耐药中的作用已得到广泛研究。然而，TRIB3 促进 ccRCC 对舒尼替尼耐药的机制尚未被探索。本研究旨在探讨 TRIB3 通过调控铁死亡增加 ccRCC 对舒尼替尼治疗敏感性的机制。生物信息学分析和实验验证表明，TRIB3 在 ccRCC 组织中显著上调，与不良预后相关。用 siRNA 转染敲低 TRIB3 抑制 ccRCC 细胞的增殖和迁移，并诱导铁死亡。舒尼替尼治疗后，TRIB3 敲低增加了细胞对舒尼替尼的敏感性，增强了舒尼替尼的抑制作用，并增加了舒尼替尼诱导的铁死亡。本研究表明，TRIB3 敲低通过靶向 SLC7A11/GPX4 通路诱导铁死亡，并增强舒尼替尼治疗 ccRCC 的疗效，为克服 ccRCC 中舒尼替尼耐药的挑战提供了新的见解和潜在策略。
