PMID- 26322231 OWN - NLM STAT- PubMed-not-MEDLINE DCOM- 20150831 LR - 20220409 IS - 2049-3002 (Print) IS - 2049-3002 (Electronic) IS - 2049-3002 (Linking) VI - 3 DP - 2015 TI - Knockout of Vdac1 activates hypoxia-inducible factor through reactive oxygen species generation and induces tumor growth by promoting metabolic reprogramming and inflammation. PG - 8 LID - 10.1186/s40170-015-0133-5 [doi] LID - 8 AB - BACKGROUND: Mitochondria are more than just the powerhouse of cells; they dictate if a cell dies or survives. Mitochondria are dynamic organelles that constantly undergo fusion and fission in response to environmental conditions. We showed previously that mitochondria of cells in a low oxygen environment (hypoxia) hyperfuse to form enlarged or highly interconnected networks with enhanced metabolic efficacy and resistance to apoptosis. Modifications to the appearance and metabolic capacity of mitochondria have been reported in cancer. However, the precise mechanisms regulating mitochondrial dynamics and metabolism in cancer are unknown. Since hypoxia plays a role in the generation of these abnormal mitochondria, we questioned if it modulates mitochondrial function. The mitochondrial outer-membrane voltage-dependent anion channel 1 (VDAC1) is at center stage in regulating metabolism and apoptosis. We demonstrated previously that VDAC1 was post-translationally C-terminal cleaved not only in various hypoxic cancer cells but also in tumor tissues of patients with lung adenocarcinomas. Cells with enlarged mitochondria and cleaved VDAC1 were also more resistant to chemotherapy-stimulated cell death than normoxic cancer cells. RESULTS: Transcriptome analysis of mouse embryonic fibroblasts (MEF) knocked out for Vdac1 highlighted alterations in not only cancer and inflammatory pathways but also in the activation of the hypoxia-inducible factor-1 (HIF-1) signaling pathway in normoxia. HIF-1alpha was stable in normoxia due to accumulation of reactive oxygen species (ROS), which decreased respiration and glycolysis and maintained basal apoptosis. However, in hypoxia, activation of extracellular signal-regulated kinase (ERK) in combination with maintenance of respiration and increased glycolysis counterbalanced the deleterious effects of enhanced ROS, thereby allowing Vdac1 (-/-) MEF to proliferate better than wild-type MEF in hypoxia. Allografts of RAS-transformed Vdac1 (-/-) MEF exhibited stabilization of both HIF-1alpha and HIF-2alpha, blood vessel destabilization, and a strong inflammatory response. Moreover, expression of Cdkn2a, a HIF-1-target and tumor suppressor gene, was markedly decreased. Consequently, RAS-transformed Vdac1 (-/-) MEF tumors grew faster than wild-type MEF tumors. CONCLUSIONS: Metabolic reprogramming in cancer cells may be regulated by VDAC1 through vascular destabilization and inflammation. These findings provide new perspectives into the understanding of VDAC1 in the function of mitochondria not only in cancer but also in inflammatory diseases. FAU - Brahimi-Horn, M Christiane AU - Brahimi-Horn MC AD - Institute for Research on Cancer and Aging of Nice, CNRS-UMR 7284-Inserm U1081, University of Nice Sophia-Antipolis, Centre Antoine Lacassagne, 33 Ave de Valombrose, 06189 Nice, France. FAU - Giuliano, Sandy AU - Giuliano S AD - Institute for Research on Cancer and Aging of Nice, CNRS-UMR 7284-Inserm U1081, University of Nice Sophia-Antipolis, Centre Antoine Lacassagne, 33 Ave de Valombrose, 06189 Nice, France. FAU - Saland, Estelle AU - Saland E AD - Centre de Recherche en Cancerologie de Toulouse, INSERM-UPSIII U1037, Oncopole, Toulouse, 31037 Cedex 1 France. FAU - Lacas-Gervais, Sandra AU - Lacas-Gervais S AD - Centre Commun de Microscopie Appliquee, University of Nice Sophia-Antipolis, 28 Ave Valombrose, 06103 Nice, France. FAU - Sheiko, Tatiana AU - Sheiko T AD - Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, MS BCM225, Houston, TX 77030 USA. FAU - Pelletier, Joffrey AU - Pelletier J AD - Institute for Research on Cancer and Aging of Nice, CNRS-UMR 7284-Inserm U1081, University of Nice Sophia-Antipolis, Centre Antoine Lacassagne, 33 Ave de Valombrose, 06189 Nice, France. FAU - Bourget, Isabelle AU - Bourget I AD - Institute for Research on Cancer and Aging of Nice, CNRS-UMR 7284-Inserm U1081, University of Nice Sophia-Antipolis, 28 Ave de Valombrose, 06107 cedex 02 Nice, France. FAU - Bost, Frederic AU - Bost F AD - INSERM U1065, Centre Mediterraneen de Medecine Moleculaire (C3M), Team Cellular and Molecular Physiopathology of Obesity and Diabetes, and University of Nice Sophia-Antipolis, Nice, France. FAU - Feral, Chloe AU - Feral C AD - Institute for Research on Cancer and Aging of Nice, CNRS-UMR 7284-Inserm U1081, University of Nice Sophia-Antipolis, 28 Ave de Valombrose, 06107 cedex 02 Nice, France. FAU - Boulter, Etienne AU - Boulter E AD - Institute for Research on Cancer and Aging of Nice, CNRS-UMR 7284-Inserm U1081, University of Nice Sophia-Antipolis, 28 Ave de Valombrose, 06107 cedex 02 Nice, France. FAU - Tauc, Michel AU - Tauc M AD - Faculte de Medecine, LP2M - CNRS UMR-7370, Universite de Nice Sophia Antipolis, 28 Avenue de Valombrose, Nice, 06107 cedex 2 France. FAU - Ivan, Mircea AU - Ivan M AD - Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN 46202 USA. FAU - Garmy-Susini, Barbara AU - Garmy-Susini B AD - Institute of Metabolic and Cardiovascular Diseases, INSERM U1048, Rangueil Hospital, 1 Avenue Professeur Jean Poulhes, BP 84225, 31432 Cedex 4 Toulouse, France. FAU - Popa, Alexandra AU - Popa A AD - Institut de Pharmacologie Moleculaire et Cellulaire (IPMC), Centre National de la Recherche Scientifique, CNRS UMR 7275, Sophia Antipolis, & University of Nice Sophia-Antipolis, Nice, France. FAU - Mari, Bernard AU - Mari B AD - Institut de Pharmacologie Moleculaire et Cellulaire (IPMC), Centre National de la Recherche Scientifique, CNRS UMR 7275, Sophia Antipolis, & University of Nice Sophia-Antipolis, Nice, France. FAU - Sarry, Jean-Emmanuel AU - Sarry JE AD - Centre de Recherche en Cancerologie de Toulouse, INSERM-UPSIII U1037, Oncopole, Toulouse, 31037 Cedex 1 France. FAU - Craigen, William J AU - Craigen WJ AD - Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, MS BCM225, Houston, TX 77030 USA. FAU - Pouyssegur, Jacques AU - Pouyssegur J AD - Institute for Research on Cancer and Aging of Nice, CNRS-UMR 7284-Inserm U1081, University of Nice Sophia-Antipolis, Centre Antoine Lacassagne, 33 Ave de Valombrose, 06189 Nice, France. AD - Centre Scientifique de Monaco (CSM), Monte Carlo, Sophia Antipolis, Monaco. FAU - Mazure, Nathalie M AU - Mazure NM AD - Institute for Research on Cancer and Aging of Nice, CNRS-UMR 7284-Inserm U1081, University of Nice Sophia-Antipolis, Centre Antoine Lacassagne, 33 Ave de Valombrose, 06189 Nice, France. LA - eng GR - R01 CA155332/CA/NCI NIH HHS/United States PT - Journal Article DEP - 20150826 PL - England TA - Cancer Metab JT - Cancer & metabolism JID - 101607582 PMC - PMC4551760 EDAT- 2015/09/01 06:00 MHDA- 2015/09/01 06:01 PMCR- 2015/08/26 CRDT- 2015/09/01 06:00 PHST- 2015/01/09 00:00 [received] PHST- 2015/05/20 00:00 [accepted] PHST- 2015/09/01 06:00 [entrez] PHST- 2015/09/01 06:00 [pubmed] PHST- 2015/09/01 06:01 [medline] PHST- 2015/08/26 00:00 [pmc-release] AID - 133 [pii] AID - 10.1186/s40170-015-0133-5 [doi] PST - epublish SO - Cancer Metab. 2015 Aug 26;3:8. doi: 10.1186/s40170-015-0133-5. eCollection 2015.