title: Knockout of Vdac1 activates hypoxia-inducible factor through reactive oxygen species generation and induces tumor growth by promoting metabolic reprogramming and inflammation.
abstract: 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-1α 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-1α and HIF-2α, 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.
authors: 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.
authors: M Christiane
authors: MC
authors: Brahimi-Horn
authors: 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.
authors: Sandy
authors: S
authors: Giuliano
authors: Centre de Recherche en Cancérologie de Toulouse, INSERM-UPSIII U1037, Oncopole, Toulouse, 31037 Cedex 1 France.
authors: Estelle
authors: E
authors: Saland
authors: Centre Commun de Microscopie Appliquée, University of Nice Sophia-Antipolis, 28 Ave Valombrose, 06103 Nice, France.
authors: Sandra
authors: S
authors: Lacas-Gervais
authors: Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, MS BCM225, Houston, TX 77030 USA.
authors: Tatiana
authors: T
authors: Sheiko
authors: 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.
authors: Joffrey
authors: J
authors: Pelletier
authors: 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.
authors: Isabelle
authors: I
authors: Bourget
authors: INSERM U1065, Centre Méditerranéen de Médecine Moléculaire (C3M), Team Cellular and Molecular Physiopathology of Obesity and Diabetes, and University of Nice Sophia-Antipolis, Nice, France.
authors: Frédéric
authors: F
authors: Bost
authors: 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.
authors: Chloé
authors: C
authors: Féral
authors: 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.
authors: Etienne
authors: E
authors: Boulter
authors: Faculté de Médecine, LP2M - CNRS UMR-7370, Université de Nice Sophia Antipolis, 28 Avenue de Valombrose, Nice, 06107 cedex 2 France.
authors: Michel
authors: M
authors: Tauc
authors: Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN 46202 USA.
authors: Mircea
authors: M
authors: Ivan
authors: Institute of Metabolic and Cardiovascular Diseases, INSERM U1048, Rangueil Hospital, 1 Avenue Professeur Jean Poulhes, BP 84225, 31432 Cedex 4 Toulouse, France.
authors: Barbara
authors: B
authors: Garmy-Susini
authors: Institut de Pharmacologie Moléculaire et Cellulaire (IPMC), Centre National de la Recherche Scientifique, CNRS UMR 7275, Sophia Antipolis, & University of Nice Sophia-Antipolis, Nice, France.
authors: Alexandra
authors: A
authors: Popa
authors: Institut de Pharmacologie Moléculaire et Cellulaire (IPMC), Centre National de la Recherche Scientifique, CNRS UMR 7275, Sophia Antipolis, & University of Nice Sophia-Antipolis, Nice, France.
authors: Bernard
authors: B
authors: Mari
authors: Centre de Recherche en Cancérologie de Toulouse, INSERM-UPSIII U1037, Oncopole, Toulouse, 31037 Cedex 1 France.
authors: Jean-Emmanuel
authors: JE
authors: Sarry
authors: Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, MS BCM225, Houston, TX 77030 USA.
authors: William J
authors: WJ
authors: Craigen
authors: 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.|Centre Scientifique de Monaco (CSM), Monte Carlo, Sophia Antipolis, Monaco.
authors: Jacques
authors: J
authors: Pouysségur
authors: 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.
authors: Nathalie M
authors: NM
authors: Mazure