PRDX1通过与Cullin-3结合作为分子伴侣抑制结直肠癌中的铁死亡

PRDX1 inhibits ferroptosis by binding to Cullin-3 as a molecular chaperone in colorectal cancer

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International Journal of Biological Sciences

影响因子:10

分区:生物学1区 Top / 生化与分子生物学2区

发表日期:2024

作者: Yujia Song, Xiaohui Wang, Yuqi Sun, Nianhua Yu, Yajie Tian, Jinli Han, Xianjun Qu, Xinfeng Yu

DOI: 10.7150/ijbs.99804

摘要

过氧化物酶还原酶1（PRDX1）是一种强效的抗氧化蛋白，具有独特的分子伴侣活性。然而，PRDX1在结直肠癌（CRC）中过表达的作用尚不明确。研究发现，PRDX1敲除小鼠中AOM/DSS诱导的结直肠炎相关癌的数量显著低于野生型小鼠，并伴随NRF2和GPX4的下调。从机制上看，RNA测序结果显示，敲低PRDX1显著减少NRF2，进一步引发ROS诱导的线粒体功能障碍和脂质过氧化引起的铁死亡。值得注意的是，PRDX1抑制NRF2的降解并促进其核转移，从而激活GPX4的转录。免疫沉淀-质谱（IP-MS）和共免疫沉淀（Co-IP）实验显示，PRDX1可以通过结合CUL3作为分子伴侣，抑制NRF2的泛素化。PRDX1与CUL3的结合在Conoidin A存在时增强，在PRDX1的Cys83Ser突变体中则被破坏。PRDX1敲低对CRC的抑制作用可以通过NRF2激活或Ferrostatin-1在体内的应用得到缓解。总体而言，这些结果揭示了PRDX1作为分子伴侣，通过抑制CUL3介导的NRF2降解，促进CRC进展的新机制，PRDX1的Cys83可能成为抑制CRC的潜在药物靶点。

Abstract

Peroxiredoxin 1 (PRDX1) is a potent antioxidant protein that displays a unique molecular chaperone activity. However, the role of overexpression of PRDX1 in colorectal cancer (CRC) was elusive. Herein, we found that the number of AOM/DSS-induced colitis-associated CRC in PRDX1 knockout mice was significantly lower than that in wild-type mice, concomitant with the downregulation of NRF2 and GPX4. Mechanistically, RNA sequencing results indicated that knockdown of PRDX1 resulted in a significant reduction of NRF2, which further triggered ROS-induced mitochondrial dysfunction and lipid peroxidation-induced ferroptosis in CRC cells. Notably, PRDX1 inhibited NRF2 degradation and promoted NRF2 nuclear translocation, thereby triggering the transcription of GPX4. Immunoprecipitation-mass spectrometry (IP-MS) and Co-immunoprecipitation (Co-IP) assays revealed that PRDX1 could act as a molecular chaperone by binding to CUL3 to inhibit NRF2 ubiquitination. Importantly, the binding of PRDX1 to CUL3 was enhanced by conoidin A but abolished by the PRDX1 Cys83Ser mutant. The inhibitory effects of PRDX1 knockdown on CRC could be attenuated by NRF2 activation or ferrostatin-1 administration in vivo. Collectively, these results provide a novel insight into the molecular chaperone activity of PRDX1 in promoting CRC progression through suppression of CUL3-mediated NRF2 degradation, suggesting PRDX1 Cys83 is a potential drug target in inhibiting CRC.