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TRIB3 knockdown increases the sensitivity of clear cell renal cell carcinoma to sunitinib by inducing ferroptosis
Zixuan Chen1, Xing Jia1, Zhou Wang1
1Department of Urology, Tongren Hospital Shanghai Jiao Tong University School of Medicine, Shanghai 200336, China.
Abstract:
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.
Insights
This study reveals TRIB3 drives sunitinib resistance in clear cell renal cell carcinoma (ccRCC) by inhibiting ferroptosis. Targeting TRIB3 enhances sunitinib efficacy, offering a new strategy against ccRCC drug resistance.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Therapeutics
Background:
- Sunitinib resistance is a major obstacle in clear cell renal cell carcinoma (ccRCC) treatment.
- The oncogene TRIB3's role in drug resistance is known, but its mechanism in ccRCC sunitinib resistance is unexplored.
Purpose of the Study:
- To investigate how TRIB3 regulates ferroptosis to overcome sunitinib resistance in ccRCC.
- To explore TRIB3 as a potential therapeutic target for improving ccRCC treatment outcomes.
Main Methods:
- Bioinformatics analysis of ccRCC tissues.
- Experimental validation using siRNA transfection to knockdown TRIB3.
- Assessment of ccRCC cell proliferation, migration, and ferroptosis.
- Evaluation of cell sensitivity to sunitinib treatment.
Main Results:
- TRIB3 is upregulated in ccRCC and linked to poor prognosis.
- TRIB3 knockdown inhibited ccRCC cell proliferation and migration, inducing ferroptosis.
- TRIB3 knockdown sensitized ccRCC cells to sunitinib, enhancing its therapeutic effect and ferroptosis induction.
- TRIB3 knockdown targets the SLC7A11/GPX4 pathway, inducing ferroptosis.
Conclusions:
- TRIB3 knockdown induces ferroptosis via the SLC7A11/GPX4 pathway, enhancing sunitinib efficacy in ccRCC.
- Targeting TRIB3 presents a promising strategy to overcome sunitinib resistance in ccRCC treatment.
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