Temsirolimus 可抑制 FSP1 酶的活性,从而诱导铁变态反应,抑制肝癌的进展。

IF 5.3 2区 生物学 Q2 CELL BIOLOGY Journal of Molecular Cell Biology Pub Date : 2024-09-23 DOI:10.1093/jmcb/mjae036
Rui-Lin Tian, Tian-Xiang Wang, Zi-Xuan Huang, Zhen Yang, Kun-Liang Guan, Yue Xiong, Pu Wang, Dan Ye
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引用次数: 0

摘要

铁凋亡是一种非凋亡性细胞死亡模式,其特点是铁依赖性脂质过氧化物的积累。由谷胱甘肽过氧化物酶 4(GPX4)催化的脂质自由基消除反应是一种主要的抗铁细胞凋亡机制,通过药物抑制这一途径有望成为一种抗肿瘤策略。然而,某些肿瘤细胞在脂质自由基消除途径上表现出冗余性,导致它们对 GPX4 抑制剂无反应。在这项研究中,我们对不同的癌细胞系和美国食品与药物管理局(FDA)批准的药物进行了筛选,最终发现替米考星(temsirolimus)与 GPX4 抑制剂 RSL3 联用可有效诱导肝癌细胞中的铁变态反应。从机理上讲,替米考星通过直接结合和抑制铁氧化抑制蛋白1(FSP1)酶,使肝癌细胞对铁氧化敏感。值得注意的是,虽然替莫司被认为是一种强效的mTOR抑制剂,但其诱导铁变态反应的作用主要归因于对FSP1的抑制,而不是mTOR活性。通过体外集落形成试验和体内肿瘤异种移植模型,我们证明了替西罗莫司和 RSL3 的组合能有效抑制肝脏肿瘤的进展。这种杀瘤作用与脂质过氧化反应的增加和铁变态反应的诱导有关。总之,我们的研究结果强调了结合多靶点铁蛋白沉降诱导剂来规避肝癌细胞对铁蛋白沉降的耐药性的潜力,并突出了替西罗莫司作为一种有前景的FSP1抑制剂和铁蛋白沉降诱导剂,在转化医学中也值得进一步研究。
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Temsirolimus inhibits FSP1 enzyme activity to induce ferroptosis and restrain liver cancer progression.

Ferroptosis is a non-apoptotic mode of cell death characterized by iron-dependent accumulation of lipid peroxidation. While lipid radical elimination reaction catalyzed by glutathione peroxidase 4 (GPX4) is a major anti-ferroptosis mechanism, inhibiting this pathway pharmaceutically shows promise as an anti-tumor strategy. However, certain tumor cells exhibit redundancy in lipid radical elimination pathways, rendering them unresponsive to GPX4 inhibitors. In this study, we conducted screens across different cancer cell lines and FDA-approved drugs, leading to the identification of temsirolimus in combination with the GPX4 inhibitor RSL3 as a potent inducer of ferroptosis in liver cancer cells. Mechanistically, temsirolimus sensitized liver cancer cells to ferroptosis by directly binding to and inhibiting ferroptosis suppressor protein 1 (FSP1) enzyme. Notably, while temsirolimus is recognized as a potent mTOR inhibitor, its ferroptosis-inducing effect is primarily attributed to its inhibition of FSP1 rather than mTOR activity. By performing in vitro colony formation assays and in vivo tumor xenograft models, we demonstrated that the combination of temsirolimus and RSL3 effectively suppressed liver tumor progression. This tumoricidal effect was associated with increased lipid peroxidation and induction of ferroptosis. In conclusion, our findings underscore the potential of combining multi-target ferroptosis-inducing agents to circumvent resistance to ferroptosis in liver cancer cells and highlight temsirolimus as a promising FSP1 inhibitor and ferroptosis inducer, which also deserves further investigation in translational medicine.

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来源期刊
CiteScore
9.60
自引率
1.80%
发文量
1383
期刊介绍: The Journal of Molecular Cell Biology ( JMCB ) is a full open access, peer-reviewed online journal interested in inter-disciplinary studies at the cross-sections between molecular and cell biology as well as other disciplines of life sciences. The broad scope of JMCB reflects the merging of these life science disciplines such as stem cell research, signaling, genetics, epigenetics, genomics, development, immunology, cancer biology, molecular pathogenesis, neuroscience, and systems biology. The journal will publish primary research papers with findings of unusual significance and broad scientific interest. Review articles, letters and commentary on timely issues are also welcome. JMCB features an outstanding Editorial Board, which will serve as scientific advisors to the journal and provide strategic guidance for the development of the journal. By selecting only the best papers for publication, JMCB will provide a first rate publishing forum for scientists all over the world.
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