VDAC1: from structure to cancer therapy

Abstract

Here, we review current evidence pointing to the function of VDAC1 in cell life and death, and highlight these functions in relation to cancer. Found at the outer mitochondrial membrane, VDAC1 assumes a crucial position in the cell, controlling the metabolic cross-talk between mitochondria and the rest of the cell. Moreover, its location at the boundary between the mitochondria and the cytosol enables VDAC1 to interact with proteins that mediate and regulate the integration of mitochondrial functions with other cellular activities. As a metabolite transporter, VDAC1 contributes to the metabolic phenotype of cancer cells. This is reflected by VDAC1 over-expression in many cancer types, and by inhibition of tumor development upon silencing VDAC1 expression. Along with regulating cellular energy production and metabolism, VDAC1 is also a key protein in mitochondria-mediated apoptosis, participating in the release of apoptotic proteins and interacting with anti-apoptotic proteins. The involvement of VDAC1 in the release of apoptotic proteins located in the inter-membranal space is discussed, as is VDAC1 oligomerization as an important step in apoptosis induction. VDAC also serves as an anchor point for mitochondria-interacting proteins, some of which are also highly expressed in many cancers, such as hexokinase (HK), Bcl2, and Bcl-xL. By binding to VDAC, HK provides both metabolic benefit and apoptosis-suppressive capacity that offers the cell a proliferative advantage and increases its resistance to chemotherapy. VDAC1-based peptides that bind specifically to HK, Bcl2, or Bcl-xL abolished the cell’s abilities to bypass the apoptotic pathway. Moreover, these peptides promote cell death in a panel of genetically characterized cell lines derived from different human cancers. These and other functions point to VDAC1 as a rational target for the development of a new generation of therapeutics.

NAF-1 and mitoNEET are central to human breast cancer proliferation by maintaining mitochondrial homeostasis and promoting tumor growth

“…Contrary to previously held beliefs, recent studies have demonstrated that mitochondria are also key players in the transformation process of cancer cells and may be used as targets for anticancer therapy (2)(3)(4)(5)(6). The involvement of mitochondria in cancer cell function could be linked to the enhanced accumulation of iron and reactive oxygen species (ROS) in mitochondria of cancer cells, which is thought to result from the increased metabolic and energetic demands of the transformed phenotype (7).…”

Molecular Targets of Cannabidiol in Neurological Disorders

“…Moreover, mitochondrial bioenergetics may also be modified by CBD via interaction with mitochondrial voltage-dependent anion channel 1 (VDAC1; see BIon Channels^) [84], which may affect the production of adenosine triphosphate (ATP). VDAC1 is involved in the transport of ions (e.g., calcium) and multiple metabolites, including adenosine diphosphate [85], the substrate of ATP. There are still some discrepancies surrounding the nature of CBD's action on the complexes comprising the ETC.…”

Molecular Mechanisms of Apoptosis and Roles in Cancer Development and Treatment

“…Tajeddine N. et al reported that knockdown of the VDAC1 was able to inhibit cell death induced by cisplatin (Tajeddine et al, 2008). In addition, Arbel N. et al have demonstrated that direct interaction of anti-apoptotic Bcl-2 and Bcl-xL with VDAC results in decreased channel conductance and causes anti-apoptotic actions (Arbel et al, 2012).Thus, searching for compounds that block the binding of VDAC1 and prosurvival/antiapoptotic hexokinase (HK) and Bcl-2 family proteins may be promising targets for anticancer drug research (Shoshan-Barmatz and Mizrachi, 2012). Recently, Prezma T. et al have designed VDAC1-based cell-penetrating peptides which target HK, Bcl-2 and Bcl-xL to inhibit the interaction of VDAC1 and the anti-apoptotic proteins in B-cell CLL (Prezma et al, 2013).…”