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

IF 4.4 2区生物学 Q2 CELL BIOLOGY Cellular signalling Pub Date : 2024-09-17 DOI:10.1016/j.cellsig.2024.111421

Zixuan Chen , Xing Jia , Zhou Wang , Yuesong Cai , An Xu , Chengtao Han , Sheng Cheng , Min Liu

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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.

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TRIB3基因敲除可通过诱导铁变态反应提高透明细胞肾细胞癌对舒尼替尼的敏感性

舒尼替尼耐药性是治疗透明细胞肾细胞癌（ccRCC）的一大挑战。TRIB3是一种新发现的癌基因，它在肿瘤耐药性中的作用已被广泛研究。然而，TRIB3在ccRCC中导致舒尼替尼耐药的机制尚未被探索。本研究旨在探究TRIB3通过调控铁凋亡增加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显示，TRIB3在ccRCC组织中显著上调，并与不良预后相关。使用 siRNA 转染技术敲除 TRIB3 可抑制 ccRCC 细胞的增殖和迁移，并诱导铁变态反应。在舒尼替尼治疗后，TRIB3的敲除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，并增强了舒尼替尼诱导的铁变态反应。这项研究表明，TRIB3基因敲除通过靶向SLC7A11/GPX4通路诱导铁蛋白沉积，增强了舒尼替尼对ccRCC的疗效，为克服ccRCC对舒尼替尼耐药的挑战提供了新的见解和潜在的策略。

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来源期刊

Cellular signalling 生物-细胞生物学

CiteScore

8.40

自引率

0.00%

发文量

250

审稿时长

27 days

期刊介绍： Cellular Signalling publishes original research describing fundamental and clinical findings on the mechanisms, actions and structural components of cellular signalling systems in vitro and in vivo. Cellular Signalling aims at full length research papers defining signalling systems ranging from microorganisms to cells, tissues and higher organisms.