VDAC1 is found at the crossroads of metabolic and survival pathways. VDAC1 controls metabolic cross-talk between mitochondria and the rest of the cell by allowing the influx and efflux of metabolites,
ions,
nucleotides, Ca2+ and more. The location of VDAC1 at the outer mitochondrial membrane also enables its interaction with
proteins that mediate and regulate the integration of mitochondrial functions with cellular activities. As a transporter of metabolites, VDAC1 contributes to the metabolic phenotype of
cancer cells. Indeed, this
protein is over-expressed in many
cancer types, and silencing of VDAC1 expression induces an inhibition of
tumor development. At the same time, along with regulating cellular energy production and metabolism, VDAC1 is involved in the process of mitochondria-mediated apoptosis by mediating the release of apoptotic
proteins and interacting with
anti-apoptotic proteins. The engagement of VDAC1 in the release of apoptotic
proteins located in the inter-membranal space involves VDAC1 oligomerization that mediates the release of
cytochrome c and AIF to the cytosol, subsequently leading to apoptotic cell death. Apoptosis can also be regulated by VDAC1, serving as an anchor point for mitochondria-interacting
proteins, such as
hexokinase (HK), Bcl2 and Bcl-xL, some of which are also highly expressed in many
cancers. By binding to VDAC1, HK provides both a metabolic benefit and apoptosis-suppressive capacity that offer the cell a proliferative advantage and increase its resistance to
chemotherapy. Thus, these and other functions point to VDAC1 as an excellent target for impairing the re-programed metabolism of
cancer cells and their ability to evade apoptosis. Here, we review current evidence pointing to the function of VDAC1 in cell life and death, and highlight these functions in relation to both
cancer development and
therapy. In addressing the recently solved 3D structures of VDAC1, this review will point to structure-function relationships of VDAC as critical for deciphering how this channel can perform such a variety of roles, all of which are important for cell life and death. Finally, this review will also provide insight into VDAC function in Ca2+ homeostasis, protection against oxidative stress, regulation of apoptosis and involvement in several diseases, as well as its role in the action of different drugs. We will discuss the use of VDAC1-based strategies to attack the altered metabolism and apoptosis of
cancer cells. These strategies include specific
siRNA able to impair energy and metabolic homeostasis, leading to arrested
cancer cell growth and
tumor development, as well VDAC1-based
peptides that interact with
anti-apoptotic proteins to induce apoptosis, thereby overcoming the resistance of
cancer cell to
chemotherapy. Finally, small molecules targeting VDAC1 can induce apoptosis. VDAC1 can thus be considered as standing at the crossroads between mitochondrial metabolite transport and apoptosis and hence represents an emerging
cancer drug target. This article is part of a Special Issue entitled:
Membrane channels and transporters in
cancers.