National Institute for Biotechnology in the Negev, Ben-Gurion University of the Negev, Beer Sheva 84105, Israel.
Department of Life Sciences, Ben-Gurion University of the Negev, Beer Sheva 84105, Israel.
Biomolecules. 2024 Sep 9;14(9):1139. doi: 10.3390/biom14091139.
This review presents current knowledge related to the voltage-dependent anion channel-1 (VDAC1) as a multi-functional mitochondrial protein that acts in regulating both cell life and death. The location of VDAC1 at the outer mitochondrial membrane (OMM) allows control of metabolic cross-talk between the mitochondria and the rest of the cell, and also enables its interaction with proteins that are involved in metabolic, cell death, and survival pathways. VDAC1's interactions with over 150 proteins can mediate and regulate the integration of mitochondrial functions with cellular activities. To target these protein-protein interactions, VDAC1-derived peptides have been developed. This review focuses specifically on cell-penetrating VDAC1-based peptides that were developed and used as a "decoy" to compete with VDAC1 for its VDAC1-interacting proteins. These peptides interfere with VDAC1 interactions, for example, with metabolism-associated proteins such as hexokinase (HK), or with anti-apoptotic proteins such as Bcl-2 and Bcl-xL. These and other VDAC1-interacting proteins are highly expressed in many cancers. The VDAC1-based peptides in cells in culture selectively affect cancerous, but not non-cancerous cells, inducing cell death in a variety of cancers, regardless of the cancer origin or genetics. They inhibit cell energy production, eliminate cancer stem cells, and act very rapidly and at low micro-molar concentrations. The activity of these peptides has been validated in several mouse cancer models of glioblastoma, lung, and breast cancers. Their anti-cancer activity involves a multi-pronged attack targeting the hallmarks of cancer. They were also found to be effective in treating non-alcoholic fatty liver disease and diabetes mellitus. Thus, VDAC1-based peptides, by targeting VDAC1-interacting proteins, offer an affordable and innovative new conceptual therapeutic paradigm that can potentially overcome heterogeneity, chemoresistance, and invasive metastatic formation.
这篇综述介绍了电压依赖性阴离子通道 1（VDAC1）作为一种多功能线粒体蛋白的最新知识，该蛋白在调节细胞生死中发挥作用。VDAC1 位于线粒体外膜（OMM）上，可控制线粒体与细胞其余部分之间的代谢串扰，还使其能够与参与代谢、细胞死亡和存活途径的蛋白质相互作用。VDAC1 与超过 150 种蛋白质的相互作用可以介导和调节线粒体功能与细胞活动的整合。为了靶向这些蛋白-蛋白相互作用，已经开发了 VDAC1 衍生肽。本综述专门关注穿透细胞的基于 VDAC1 的肽，这些肽被开发并用作“诱饵”，与 VDAC1 竞争其 VDAC1 相互作用蛋白。这些肽干扰 VDAC1 的相互作用，例如与代谢相关的蛋白，如己糖激酶（HK），或与抗凋亡蛋白，如 Bcl-2 和 Bcl-xL。这些和其他 VDAC1 相互作用蛋白在许多癌症中高度表达。基于 VDAC1 的肽在培养的细胞中选择性地影响癌性细胞，而不是非癌性细胞，在各种癌症中诱导细胞死亡，无论癌症起源或遗传学如何。它们抑制细胞能量产生，消除癌症干细胞，并以非常快速和低微摩尔浓度起作用。这些肽在几种小鼠癌症模型（包括胶质母细胞瘤、肺癌和乳腺癌）中已得到验证。它们的抗癌活性涉及针对癌症特征的多管齐下的攻击。它们还被发现对非酒精性脂肪性肝病和糖尿病有效。因此，基于 VDAC1 的肽通过靶向 VDAC1 相互作用蛋白，提供了一种负担得起且创新的新概念治疗范式，有可能克服异质性、化疗耐药性和侵袭性转移性形成。
