At the crossroads between mitochondrial metabolite transport and apoptosis: Vdac1 as an emerging cancer drug target

Many cancer cells undergo re-programing of metabolism and develop cell survival strategies involving anti-apoptotic defense mechanisms, a hallmark of a great majority of cancer types. The voltage-dependent anion channel 1 (VDAC1), an outer mitochondria membrane protein, serves as a mitochondrial gatekeeper, controlling the metabolic and energy cross-talk between mitochondria and the rest of the cell. VDAC1 has also been recognized as a key protein in mitochondria-mediated apoptosis due to its association with pro- and anti-apoptotic members of the Bcl-2 family of proteins. At the same time, VDAC1 functions in the release of apoptotic proteins located in the inter-membranal space. Thus, VDAC1 is emerging 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 cancer therapy. We discuss the use of VDAC1-based strategies to attack the altered metabolism and apoptosis of cancer cells. These strategies include specific siRNA to impair energy and metabolic homeostasis, leading to arrest cancer cell growth and tumor development, as well as VDAC1-based peptides interacting with anti-apoptotic proteins and inducing 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.