揭示神经酰胺导致细胞死亡的分子原理

IF 4.1 Q2 CELL BIOLOGY Cell Stress Pub Date : 2019-07-16 DOI:10.15698/cst2019.08.196
Shashank Dadsena, Dina G. Hassan, J. Holthuis
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引用次数: 12

摘要

神经酰胺是鞘脂代谢的中心中间体,可以激活多种肿瘤抑制细胞程序,包括细胞周期停滞、衰老和凋亡。事实上,神经酰胺生成和周转的扰动通常与癌症细胞的存活和化疗耐药性有关。因此,神经酰胺治疗癌症的潜力已成为人们关注的主要焦点。越来越多的证据表明,神经酰胺可以直接作用于线粒体,引发细胞凋亡。然而,关于潜在机制的分子细节却很少。在我们最近的研究中(Dadsena S et al.,2019,Nat Commun 10:1832),我们使用可光活化神经酰胺探针,结合计算机模拟和功能研究,确定电压依赖性阴离子通道VDAC2是神经酰胺诱导的线粒体凋亡的关键效应器。总之,我们的发现为神经酰胺如何发挥其广受好评的抗肿瘤活性提供了一个新的分子框架。
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Unraveling the molecular principles by which ceramides commit cells to death
Ceramides are central intermediates of sphingolipid metabolism that can activate a variety of tumor suppressive cellular programs, including cell cycle arrest, senescence and apoptosis. Indeed, perturbations in ceramide generation and turnover are frequently linked to cancer cell survival and resistance to chemotherapy. Consequently, the potential of ceramide-based therapeutics in the treatment of cancer has become a major focus of interest. A growing body of evidence indicates that ceramides can act directly on mitochondria to trigger apoptotic cell death. However, molecular details of the underlying mechanism are scarce. In our recent study (Dadsena S et al., 2019, Nat Commun 10:1832), we used a photoactivatable ceramide probe combined with computer simulations and functional studies to identify the voltage-dependent anion channel VDAC2 as a critical effector of ceramide-induced mitochondrial apoptosis. Collectively, our findings provide a novel molecular framework for how ceramides execute their widely acclaimed anti-neoplastic activities.
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来源期刊
Cell Stress
Cell Stress Biochemistry, Genetics and Molecular Biology-Biochemistry, Genetics and Molecular Biology (miscellaneous)
CiteScore
13.50
自引率
0.00%
发文量
21
审稿时长
15 weeks
期刊介绍: Cell Stress is an open-access, peer-reviewed journal that is dedicated to publishing highly relevant research in the field of cellular pathology. The journal focuses on advancing our understanding of the molecular, mechanistic, phenotypic, and other critical aspects that underpin cellular dysfunction and disease. It specifically aims to foster cell biology research that is applicable to a range of significant human diseases, including neurodegenerative disorders, myopathies, mitochondriopathies, infectious diseases, cancer, and pathological aging. The scope of Cell Stress is broad, welcoming submissions that represent a spectrum of research from fundamental to translational and clinical studies. The journal is a valuable resource for scientists, educators, and policymakers worldwide, as well as for any individual with an interest in cellular pathology. It serves as a platform for the dissemination of research findings that are instrumental in the investigation, classification, diagnosis, and therapeutic management of major diseases. By being open-access, Cell Stress ensures that its content is freely available to a global audience, thereby promoting international scientific collaboration and accelerating the exchange of knowledge within the research community.
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