The mitochondrial voltage-dependent anion channel 1 in tumor cells

Abstract

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 ...

The Voltage-dependent Anion Channel 1 Mediates Amyloid β Toxicity and Represents a Potential Target for Alzheimer Disease Therapy

“…HK bound to VDAC1 offers the enzyme direct access to mitochondrial sources of ATP and greater affinity for Mg 2ϩ -ATP (16). This is lost upon HK detachment from VDAC1 as induced by A␤.…”

“…VDAC1 transports ions, Ca 2ϩ , cholesterol, and metabolites across the outer mitochondrial membrane and participates in the release of mitochondrial pro-apoptotic proteins to the cytosol and interacts with apoptosis regulatory proteins (15,16). Thus VDAC1 appears to be a convergence point for a variety of cell survival and death signals.…”

“…Importantly, A␤ does not cause toxicity in cells depleted of mitochondria (12). Finally, the mitochondrial protein, the voltage-dependent anion channel (VDAC), was shown to participate in A␤-induced toxicity (13,14).VDAC1 transports ions, Ca 2ϩ , cholesterol, and metabolites across the outer mitochondrial membrane and participates in the release of mitochondrial pro-apoptotic proteins to the cytosol and interacts with apoptosis regulatory proteins (15,16). Thus VDAC1 appears to be a convergence point for a variety of cell survival and death signals.…”

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“…36,37 Other reports also indicate PPID overexpression in many tumor types. 38 In addition to aberrations of these genes in lymphoma, our results showed that expression of SLC25A31 could be regulated by VPA treatment.…”

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“…VDAC1, as a gatekeeper in the outer mitochondrial membrane, has the pivotal functions in cancer cells through the management of anti/pro-apoptotic proteins during intrinsic apoptosis (Shoshan-Barmatz et al 2015). Current evidence has demonstrated the participating of VDAC1 in drug resistance, carcinogenesis, cell metabolism and apoptosis (Shoshan-Barmatz et al 2015;Wang et al 2016). Low expression VDAC1 induces a non-apoptotic role and high expression VDAC1 occurs following apoptosis induction by chemotherapeutic agents .…”