PMID- 25448878 OWN - NLM STAT- MEDLINE DCOM- 20151124 LR - 20220316 IS - 0006-3002 (Print) IS - 0006-3002 (Linking) VI - 1848 IP - 10 Pt B DP - 2015 Oct TI - The mitochondrial voltage-dependent anion channel 1 in tumor cells. PG - 2547-75 LID - S0005-2736(14)00375-7 [pii] LID - 10.1016/j.bbamem.2014.10.040 [doi] AB - 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. CI - Copyright (c) 2014 Elsevier B.V. All rights reserved. FAU - Shoshan-Barmatz, Varda AU - Shoshan-Barmatz V AD - Department of Life Sciences, and the National Institute for Biotechnology in the Negev, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel. Electronic address: vardasb@bgu.ac.il. FAU - Ben-Hail, Danya AU - Ben-Hail D AD - Department of Life Sciences, and the National Institute for Biotechnology in the Negev, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel. FAU - Admoni, Lee AU - Admoni L AD - Department of Life Sciences, and the National Institute for Biotechnology in the Negev, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel. FAU - Krelin, Yakov AU - Krelin Y AD - Department of Life Sciences, and the National Institute for Biotechnology in the Negev, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel. FAU - Tripathi, Shambhoo Sharan AU - Tripathi SS AD - Department of Life Sciences, and the National Institute for Biotechnology in the Negev, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't PT - Review DEP - 20141104 PL - Netherlands TA - Biochim Biophys Acta JT - Biochimica et biophysica acta JID - 0217513 RN - 0 (Antineoplastic Agents) RN - 0 (Apoptosis Regulatory Proteins) RN - 0 (RNA, Small Interfering) RN - 0 (VDAC1 protein, human) RN - EC 1.6.- (Voltage-Dependent Anion Channel 1) RN - EC 2.7.1.1 (Hexokinase) RN - SY7Q814VUP (Calcium) SB - IM MH - Antineoplastic Agents/therapeutic use MH - Apoptosis/drug effects/genetics MH - Apoptosis Regulatory Proteins/genetics/*metabolism MH - Calcium/metabolism MH - Cell Proliferation/drug effects MH - *Gene Expression Regulation, Neoplastic MH - Hexokinase/genetics/metabolism MH - Humans MH - Mitochondria/drug effects/*metabolism MH - Mitochondrial Membranes/drug effects/*metabolism MH - Neoplasms/drug therapy/*genetics/metabolism/pathology MH - RNA, Small Interfering/genetics/metabolism MH - Signal Transduction MH - Structure-Activity Relationship MH - Tumor Cells, Cultured MH - Voltage-Dependent Anion Channel 1/antagonists & inhibitors/chemistry/genetics/*metabolism OTO - NOTNLM OT - Apoptosis OT - Cancer OT - Metabolism OT - Mitochondria OT - VDAC1 EDAT- 2014/12/03 06:00 MHDA- 2015/12/15 06:00 CRDT- 2014/12/03 06:00 PHST- 2014/07/10 00:00 [received] PHST- 2014/10/20 00:00 [revised] PHST- 2014/10/24 00:00 [accepted] PHST- 2014/12/03 06:00 [entrez] PHST- 2014/12/03 06:00 [pubmed] PHST- 2015/12/15 06:00 [medline] AID - S0005-2736(14)00375-7 [pii] AID - 10.1016/j.bbamem.2014.10.040 [doi] PST - ppublish SO - Biochim Biophys Acta. 2015 Oct;1848(10 Pt B):2547-75. doi: 10.1016/j.bbamem.2014.10.040. Epub 2014 Nov 4.