Abstract
Cancer cells share several properties, high proliferation potential, reprogramed metabolism, and resistance to apoptotic cues. Acquiring these hallmarks involves changes in key oncogenes and non-oncogenes essential for cancer cell survival and prosperity, and is accompanied by the increased energy requirements of proliferating cells. Mitochondria occupy a central position in cell life and death with mitochondrial bioenergetics, biosynthesis, and signaling are critical for tumorigenesis. Voltage-dependent anion channel 1 (VDAC1) is situated in the outer mitochondrial membrane (OMM) and serving as a mitochondrial gatekeeper. VDAC1 allowing the transfer of metabolites, fatty acid ions, Ca2+, reactive oxygen species, and cholesterol across the OMM and is a key player in mitochondrial-mediate apoptosis. Moreover, VDAC1 serves as a hub protein, interacting with diverse sets of proteins from the cytosol, endoplasmic reticulum, and mitochondria that together regulate metabolic and signaling pathways. The observation that VDAC1 is over-expressed in many cancers suggests that the protein may play a pivotal role in cancer cell survival. However, VDAC1 is also important in mitochondria-mediated apoptosis, mediating release of apoptotic proteins and interacting with anti-apoptotic proteins, such as B-cell lymphoma 2 (Bcl-2), Bcl-xL, and hexokinase (HK), which are also highly expressed in many cancers. Strategically located in a “bottleneck” position, controlling metabolic homeostasis and apoptosis, VDAC1 thus represents an emerging target for anti-cancer drugs. This review presents an overview on the multi-functional mitochondrial protein VDAC1 performing several functions and interacting with distinct sets of partners to regulate both cell life and death, and highlights the importance of the protein for cancer cell survival. We address recent results related to the mechanisms of VDAC1-mediated apoptosis and the potential of associated proteins to modulate of VDAC1 activity, with the aim of developing VDAC1-based approaches. The first strategy involves modification of cell metabolism using VDAC1-specific small interfering RNA leading to inhibition of cancer cell and tumor growth and reversed oncogenic properties. The second strategy involves activation of cancer cell death using VDAC1-based peptides that prevent cell death induction by anti-apoptotic proteins. Finally, we discuss the potential therapeutic benefits of treatments and drugs leading to enhanced VDAC1 expression or targeting VDAC1 to induce apoptosis.
Highlights
Voltage-dependent anion channel 1 (VDAC1) is important in mitochondria-mediated apoptosis, mediating release of apoptotic proteins and interacting with anti-apoptotic proteins, such as B-cell lymphoma 2 (Bcl-2), Bcl-xL, and hexokinase (HK), which are highly expressed in many cancers
This review presents an overview on the multi-functional mitochondrial protein VDAC1 performing several functions and interacting with distinct sets of partners to regulate both cell life and death, and highlights the importance of the protein for cancer cell survival
We address recent results related to the mechanisms of VDAC1-mediated apoptosis and the potential of associated proteins to modulate of VDAC1 activity, with the aim of developing VDAC1-based approaches
Summary
Three VDAC isoforms have been identified, VDAC1, VDAC2, and VDAC3, sharing ~70% identity as well as several structural and functional properties [1, 2], they are significantly different with relation to functionality [1, 3, 4]. The structure of the N-terminal domain of VDAC1, its potential role in regulating barrel shape, and its interaction with HK have been reviewed recently [59] Additional roles of this region in VDAC1 oligomerization and regulation of apoptosis [16, 51] are presented below (see VDAC1 Homo-Oligomer Forming the Cyto c Release Pathway) and as the binding site for HK, Bcl-2, and Bcl-xL (see VDAC1-Based Peptides As Potential Anti-Cancer Therapy). The function of VDAC1 in energy metabolism of cancer cells and the significance of the overexpression in many cancer cells [11] is discussed further below (see VDAC1 Expression Level and Cell Death Induction—a New Concept, Unraveling VDAC1-Based Therapies) Cholesterol is another metabolite transported across the OMM [78] (Figure 2), with VDAC1 being a component of a multi-protein complex, the transduceosome, involved in the process. TBid links extrinsic pathway to intrinsic, mitochondria-mediated apoptosis
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