TRIB3 knockdown increases the sensitivity of clear cell renal cell carcinoma to sunitinib by inducing ferroptosis

• Published in: Cellular signalling 2024-12, Vol.124, p.111421, Article 111421
• Main Authors: Chen, Zixuan, Jia, Xing, Wang, Zhou, Cai, Yuesong, Xu, An, Han, Chengtao, Cheng, Sheng, Liu, Min
• Format: Article
• Language: English
• Subjects: Amino Acid Transport System y+ - genetics; Amino Acid Transport System y+ - metabolism; Animals; Antineoplastic Agents - pharmacology; Carcinoma, Renal Cell - drug therapy; Carcinoma, Renal Cell - genetics; Carcinoma, Renal Cell - metabolism; Carcinoma, Renal Cell - pathology; Cell Cycle Proteins - genetics; Cell Cycle Proteins - metabolism; Cell Line, Tumor; Cell Movement - drug effects; Cell Proliferation - drug effects; Clear cell renal cell carcinoma; Drug Resistance, Neoplasm - drug effects; Drug Resistance, Neoplasm - genetics; Ferroptosis; Ferroptosis - drug effects; Ferroptosis - genetics; Gene Expression Regulation, Neoplastic - drug effects; Gene Knockdown Techniques; Humans; Kidney Neoplasms - drug therapy; Kidney Neoplasms - genetics; Kidney Neoplasms - metabolism; Kidney Neoplasms - pathology; Mice; Mice, Nude; Phospholipid Hydroperoxide Glutathione Peroxidase - genetics; Phospholipid Hydroperoxide Glutathione Peroxidase - metabolism; Protein Serine-Threonine Kinases - antagonists & inhibitors; Protein Serine-Threonine Kinases - genetics; Protein Serine-Threonine Kinases - metabolism; Repressor Proteins - genetics; Repressor Proteins - metabolism; Sensitivity; Sunitinib; Sunitinib - pharmacology; Sunitinib - therapeutic use; TRIB3
• ISSN: 0898-6568; 1873-3913; 1873-3913
• DOI: 10.1016/j.cellsig.2024.111421

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. •TRIB3 knockdown induces ferroptosis in ccRCC cells.•TRIB3 knockdown increases the sensitivity of ccRcc cells to sunitinib.•TRIB3 knockdown increases the sensitivity of ccRcc cells to sunitinib by regulating SLC7A11/GPX4 pathway.