title: Expression of a truncated active form of VDAC1 in lung cancer associates with hypoxic cell survival and correlates with progression to chemotherapy resistance.
abstract: Resistance to chemotherapy-induced apoptosis of tumor cells represents a major hurdle to efficient cancer therapy. Although resistance is a characteristic of tumor cells that evolve in a low oxygen environment (hypoxia), the mechanisms involved remain elusive. We observed that mitochondria of certain hypoxic cells take on an enlarged appearance with reorganized cristae. In these cells, we found that a major mitochondrial protein regulating metabolism and apoptosis, the voltage-dependent anion channel 1 (VDAC1), was linked to chemoresistance when in a truncated (VDAC1-ΔC) but active form. The formation of truncated VDAC1, which had a similar channel activity and voltage dependency as full-length, was hypoxia-inducible factor-1 (HIF-1)-dependent and could be inhibited in the presence of the tetracycline antibiotics doxycycline and minocycline, known inhibitors of metalloproteases. Its formation was also reversible upon cell reoxygenation and associated with cell survival through binding to the antiapoptotic protein hexokinase. Hypoxic cells containing VDAC1-ΔC were less sensitive to staurosporine- and etoposide-induced cell death, and silencing of VDAC1-ΔC or treatment with the tetracycline antibiotics restored sensitivity. Clinically, VDAC1-ΔC was detected in tumor tissues of patients with lung adenocarcinomas and was found more frequently in large and late-stage tumors. Together, our findings show that via induction of VDAC1-ΔC, HIF-1 confers selective protection from apoptosis that allows maintenance of ATP and cell survival in hypoxia. VDAC1-ΔC may also hold promise as a biomarker for tumor progression in chemotherapy-resistant patients.
authors.affiliation: Institute of Developmental Biology and Cancer Research, University of Nice, CNRS-UMR 6543, Centre Antoine Lacassagne, Nice, France.
authors.forename: M Christiane
authors.initials: MC
authors.lastname: Brahimi-Horn
authors.forename: Danya
authors.initials: D
authors.lastname: Ben-Hail
authors.forename: Marius
authors.initials: M
authors.lastname: Ilie
authors.forename: Pierre
authors.initials: P
authors.lastname: Gounon
authors.forename: Matthieu
authors.initials: M
authors.lastname: Rouleau
authors.forename: Véronique
authors.initials: V
authors.lastname: Hofman
authors.forename: Jérôme
authors.initials: J
authors.lastname: Doyen
authors.forename: Bernard
authors.initials: B
authors.lastname: Mari
authors.forename: Varda
authors.initials: V
authors.lastname: Shoshan-Barmatz
authors.forename: Paul
authors.initials: P
authors.lastname: Hofman
authors.forename: Jacques
authors.initials: J
authors.lastname: Pouysségur
authors.forename: Nathalie M
authors.initials: NM
authors.lastname: Mazure
mesh_terms: D000230:Adenocarcinoma / Q000378:metabolism / Q000473:pathology; D017209:Apoptosis / Q000502:physiology; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D002470:Cell Survival; D018450:Disease Progression; D019008:Drug Resistance, Neoplasm / Q000502:physiology*; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D015151:Immunoblotting; D008175:Lung Neoplasms / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D020033:Protein Isoforms / Q000378:metabolism; D014162:Transfection; D050995:Voltage-Dependent Anion Channel 1 / Q000096:biosynthesis*
chemical_list: C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D020033:Protein Isoforms; C494762:VDAC1 protein, human; D050995:Voltage-Dependent Anion Channel 1