Abstract
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.
Highlights
The relative contribution of aerobic glycolysis and oxidative phosphorylation (Oxphos) to overall adenosine triphosphate (ATP) generation, determine cancer bioenergetics
A major trigger to research in cancer metabolism were the seminal findings made in the early 20th century by the German biochemist Otto Warburg, who showed in tumor slices and ascites cancer cells, that tumors produce more lactic acid than non-tumor cells even at physiological partial pressures of oxygen (Warburg et al, 1927; Warburg, 1930)
Mitochondrial bioenergetics is regulated at multiple levels, voltage dependent anion channels (VDAC) opening in cancer cells leads to three major biological effects: maximization of full oxidation because of augmented entry of substrates into mitochondria; subsequent decrease in glycolysis due to a high cytosolic ATP/adenosine diphosphate (ADP) ratio promoted by maximum generation of mitochondrial ATP; and increased formation of reactive oxygen species (ROS) following the enhanced activity of the electron transport chain (ETC)
Summary
The relative contribution of aerobic glycolysis and oxidative phosphorylation (Oxphos) to overall ATP generation, determine cancer bioenergetics. A major trigger to research in cancer metabolism were the seminal findings made in the early 20th century by the German biochemist Otto Warburg, who showed in tumor slices and ascites cancer cells, that tumors produce more lactic acid than non-tumor cells even at physiological partial pressures of oxygen (Warburg et al, 1927; Warburg, 1930). This particular phenotype, called Warburg effect, is characterized by enhanced aerobic glycolysis. We will describe the biological effects induced by changes in the conformational states of VDAC; how an increase of VDAC conductance reverses the Warburg phenotype and promotes cell death; and the relevance of VDAC as a pharmacological target to develop novel cancer chemotherapies
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
