VDAC Modulation of Cancer Metabolism: Advances and Therapeutic Challenges.
VDAC Modulation of Cancer Metabolism: Advances and Therapeutic Challenges.
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VDAC对癌症代谢的调节：进步和治疗挑战。
DOI：
10.3389/fphys.2021.742839
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发表时间：
2021
影响因子：
4
通讯作者：
Maldonado EN
中科院分区：
文献类型：
--
作者：
Heslop KA;Milesi V;Maldonado EN
大多数阴离子代谢物，包括呼吸底物、糖酵解三磷酸腺苷（ATP）和进入线粒体的小阳离子，以及线粒体ATP移动到细胞质，通过电压依赖性阴离子通道（VDAC）穿过线粒体外膜（OMM）。VDAC的封闭状态阻断了阴离子代谢物的通过，增加了包括钙在内的小阳离子的通量。因此，通过调节阴离子和阳离子通量的大小，VDAC开放的生理或药理学调节是线粒体代谢的主要贡献者。肿瘤细胞表现出促增殖的Warburg表型，其特征是在线粒体代谢部分抑制的情况下有氧糖酵解增强。大多数人类肿瘤的异质性和灵活的代谢特性使细胞能够通过在主要的糖酵解或氧化表型之间切换来适应不断变化的能量和生物合成需求。在这里，我们描述了VDAC构象状态变化对癌症代谢的生物学影响，VDAC打开剂促进癌细胞死亡的机制，以及VDAC打开作为一个有价值的药理学靶点的优势。特别强调了游离微管蛋白对VDAC的内源性调节以及VDAC-微管蛋白拮抗剂在癌细胞中的作用。由于其功能和位置，VDAC作为开关关闭线粒体代谢（关闭状态）并增加有氧糖酵解（亲warburg），或打开线粒体代谢（开放状态）并减少糖酵解（抗warburg）。更好地了解VDAC调控在肿瘤进展中的作用，对癌症生物学和开发新的癌症化疗方法都有重要意义。
Most anionic metabolites including respiratory substrates, glycolytic adenosine triphosphate (ATP), and small cations that enter mitochondria, and mitochondrial ATP moving to the cytosol, cross the outer mitochondrial membrane (OMM) through voltage dependent anion channels (VDAC). The closed states of VDAC block the passage of anionic metabolites, and increase the flux of small cations, including calcium. Consequently, physiological or pharmacological regulation of VDAC opening, by conditioning the magnitude of both anion and cation fluxes, is a major contributor to mitochondrial metabolism. Tumor cells display a pro-proliferative Warburg phenotype characterized by enhanced aerobic glycolysis in the presence of partial suppression of mitochondrial metabolism. The heterogeneous and flexible metabolic traits of most human tumors render cells able to adapt to the constantly changing energetic and biosynthetic demands by switching between predominantly glycolytic or oxidative phenotypes. Here, we describe the biological consequences of changes in the conformational state of VDAC for cancer metabolism, the mechanisms by which VDAC-openers promote cancer cell death, and the advantages of VDAC opening as a valuable pharmacological target. Particular emphasis is given to the endogenous regulation of VDAC by free tubulin and the effects of VDAC-tubulin antagonists in cancer cells. Because of its function and location, VDAC operates as a switch to turn-off mitochondrial metabolism (closed state) and increase aerobic glycolysis (pro-Warburg), or to turn-on mitochondrial metabolism (open state) and decrease glycolysis (anti-Warburg). A better understanding of the role of VDAC regulation in tumor progression is relevant both for cancer biology and for developing novel cancer chemotherapies.
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影响因子：
5.9
作者：
Brahimi-Horn MC;Giuliano S;Saland E;Lacas-Gervais S;Sheiko T;Pelletier J;Bourget I;Bost F;Féral C;Boulter E;Tauc M;Ivan M;Garmy-Susini B;Popa A;Mari B;Sarry JE;Craigen WJ;Pouysségur J;Mazure NM
通讯作者：
Mazure NM
影响因子：
4
作者：
Camara AKS;Zhou Y;Wen PC;Tajkhorshid E;Kwok WM
通讯作者：
Kwok WM
DOI：
10.1016/j.bbamcr.2016.01.019
发表时间：
2016-10-01
影响因子：
5.1
作者：
Colombini, Marco
通讯作者：
Colombini, Marco
影响因子：
4.3
作者：
Colombini, M
通讯作者：
Colombini, M
影响因子：
7.4
作者：
Bhat TA;Kumar S;Chaudhary AK;Yadav N;Chandra D
通讯作者：
Chandra D