神经酰胺诱导的代谢应激消耗富马酸盐并驱动线粒体自噬介导肿瘤抑制

IF 16.6 1区医学 Q1 ONCOLOGY

Cancer research Pub Date : 2025-06-20 DOI:10.1158/0008-5472.can-24-4042

Natalia V. Oleinik, Firdevs Cansu. Atilgan, Mohamed Faisal Kassir, Han Gyul Lee, Alhaji H. Janneh, Wyatt Wofford, Chase Walton, Zdzislaw M. Szulc, Elizabeth G. Hill, Alexander V. Alekseyenko, Huseyin Cimen, Jessica H. Hartman, Christina Voelkel-Johnson, Michael B. Lilly, John J. Lemasters, Norma Frizzell, Xue-Zhong Yu, Shikhar Mehrotra, Besim Ogretmen

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引用次数: 0

摘要

生物活性神经酰胺部分通过促进线粒体自噬诱导细胞死亡。c18 -神经酰胺水平在头颈部鳞状细胞癌（HNSCC）中普遍降低，这与预后不良相关，提示神经酰胺在癌症治疗中的潜力。在这里，我们评估了神经酰胺类似物LCL768在HNSCC中诱导线粒体自噬和代谢应激的能力。在机制上，LCL768诱导CerS1介导的内源性c18 -神经酰胺在线粒体中积累来介导线粒体自噬，这一过程不需要CerS1转运体p17/PERMIT，而是依赖于DRP1在C644的亚硝基化激活。DRP1通过促进内质网中的磷脂酰乙醇胺和线粒体膜中的心磷脂之间的联系，促进内质网和线粒体膜的锚定。Drp1的突变阻止了其与内质网和线粒体膜的结合，阻断了CerS1/ c18 -神经酰胺线粒体的积累，抑制了lcl768介导的线粒体自噬。此外，lcl768驱动的线粒体自噬改变了线粒体代谢，导致富马酸消耗，导致体内肿瘤抑制。外源性富马酸补充可阻止lcl768介导的线粒体自噬、CerS1的线粒体运输、er -线粒体栓系和小鼠肿瘤抑制。富马酸代谢与PARKIN琥珀化在催化半胱氨酸（Cys431）上相关，抑制其与PINK1和泛素的关联，从而阻止线粒体自噬。lcl768诱导富马酸耗竭减弱PARKIN琥珀化，促进PARKIN活化和线粒体自噬，表明其前馈机制通过PARKIN琥珀化调节线粒体自噬和富马酸代谢。这些数据提供了LCL768/ cers1 - c18神经酰胺介导的线粒体自噬和肿瘤抑制受Drp1亚硝基化、富马酸耗竭和PARKIN琥珀化调控的机制，为致死性线粒体自噬提供了代谢应激信号。

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Ceramide-Induced Metabolic Stress Depletes Fumarate and Drives Mitophagy to Mediate Tumor Suppression

Bioactive ceramide induces cell death in part by promoting mitophagy. C18-ceramide levels are commonly reduced in head and neck squamous cell carcinoma (HNSCC), which correlates with poor prognosis, suggesting the potential of harnessing ceramide for cancer treatment. Here, we evaluated the ability of the ceramide analog LCL768 to induce mitophagy and metabolic stress in HNSCC. Mechanistically, LCL768 induced CerS1-mediated endogenous C18-ceramide accumulation in mitochondria to mediate mitophagy, which did not require the CerS1 transporter p17/PERMIT but was dependent on DRP1 activation via nitrosylation at C644. DRP1 facilitated anchoring of the endoplasmic reticulum (ER) and mitochondrial membranes by promoting the association between phosphatidylethanolamine in the ER and cardiolipin in mitochondrial membranes. Mutations of Drp1 that prevented its binding to ER and mitochondrial membranes blocked CerS1/C18-ceramide mitochondrial accumulation, inhibiting LCL768-mediated mitophagy. In addition, LCL768-driven mitophagy altered mitochondrial metabolism, resulting in fumarate depletion and leading to tumor suppression in vivo. Exogenous fumarate supplementation prevented LCL768-mediated mitophagy, mitochondrial trafficking of CerS1, ER-mitochondrial tethering, and tumor suppression in mice. Fumarate metabolism was associated with PARKIN succination at a catalytic cysteine (Cys431), inhibiting its association with PINK1 and ubiquitin and thereby preventing mitophagy. LCL768-induced fumarate depletion attenuated PARKIN succination to promote PARKIN activation and mitophagy, indicating a feed-forward mechanism that regulates mitophagy and fumarate metabolism through PARKIN succination. These data provide a mechanism whereby LCL768/CerS1-C18-ceramide-mediated mitophagy and tumor suppression are regulated by Drp1 nitrosylation, fumarate depletion, and PARKIN succination, providing a metabolic stress signature for lethal mitophagy.

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来源期刊

Cancer research 医学-肿瘤学

CiteScore

16.10

自引率

0.90%

发文量

7677

审稿时长

2.5 months

期刊介绍： Cancer Research, published by the American Association for Cancer Research (AACR), is a journal that focuses on impactful original studies, reviews, and opinion pieces relevant to the broad cancer research community. Manuscripts that present conceptual or technological advances leading to insights into cancer biology are particularly sought after. The journal also places emphasis on convergence science, which involves bridging multiple distinct areas of cancer research. With primary subsections including Cancer Biology, Cancer Immunology, Cancer Metabolism and Molecular Mechanisms, Translational Cancer Biology, Cancer Landscapes, and Convergence Science, Cancer Research has a comprehensive scope. It is published twice a month and has one volume per year, with a print ISSN of 0008-5472 and an online ISSN of 1538-7445. Cancer Research is abstracted and/or indexed in various databases and platforms, including BIOSIS Previews (R) Database, MEDLINE, Current Contents/Life Sciences, Current Contents/Clinical Medicine, Science Citation Index, Scopus, and Web of Science.