A targetable OSGIN1 - AMPK - SLC2A3 axis controls the vulnerability of ovarian cancer to ferroptosis.

IF 6.8 1区 医学 Q1 ONCOLOGY
Mengqi Deng, Fan Tang, Xiangyu Chang, Yanqin Zhang, Penglin Liu, Xuechao Ji, Yubo Zhang, Ruiye Yang, Junyi Jiang, Junqi He, Jinwei Miao
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引用次数: 0

Abstract

Despite advances in various chemotherapy regimens, current therapeutic options are limited for ovarian cancer patients. Oxidative stress-induced growth inhibitor 1 (OSGIN1), which is a tumor suppressor gene known to regulate the cellular stress response and apoptosis, is associated with ovarian cancer development. However, the underlying mechanisms involved in ferroptosis regulation have not been elucidated. Thus, this study aimed to investigate the effect and underlying regulatory mechanism of the OSGIN1 gene on ovarian cancer cells. Our results demonstrated that loss of the OSGIN1 gene promoted ovarian cancer growth and conferred resistance to drug-induced ferroptosis. Mechanistically, the loss of OSGIN1 activates AMPK signaling through ATM, leading to the upregulation of SLC2A3, which protects cells from ferroptosis and renders them insensitive to ferroptosis inducers. Notably, an SLC2A3-neutralizing antibody enhances the ferroptosis-inducing and anticancer effects of sorafenib on ovarian cancer patient-derived xenograft tumors. Overall, anti-SLC2A3 therapy is a promising method to improve ovarian cancer treatment by targeting ferroptosis.

可靶向的OSGIN1 - AMPK - SLC2A3轴控制卵巢癌对铁下垂的易感性。
尽管各种化疗方案取得了进展,但目前卵巢癌患者的治疗选择有限。氧化应激诱导生长抑制因子1 (OSGIN1)是一种调控细胞应激反应和细胞凋亡的肿瘤抑制基因,与卵巢癌的发生发展有关。然而,涉及铁下垂调节的潜在机制尚未阐明。因此,本研究旨在探讨OSGIN1基因在卵巢癌细胞中的作用及其调控机制。我们的研究结果表明,OSGIN1基因的缺失促进了卵巢癌的生长,并赋予了对药物诱导的铁下垂的抗性。从机制上讲,OSGIN1的缺失通过ATM激活AMPK信号,导致SLC2A3上调,从而保护细胞免受铁下垂,并使其对铁下垂诱导剂不敏感。值得注意的是,slc2a3中和抗体增强了索拉非尼对卵巢癌患者来源的异种移植肿瘤的诱导铁凋亡和抗癌作用。总之,靶向铁下垂的抗slc2a3治疗是一种很有前景的改善卵巢癌治疗的方法。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
CiteScore
9.90
自引率
1.30%
发文量
87
审稿时长
18 weeks
期刊介绍: Online-only and open access, npj Precision Oncology is an international, peer-reviewed journal dedicated to showcasing cutting-edge scientific research in all facets of precision oncology, spanning from fundamental science to translational applications and clinical medicine.
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