title: Time-dependent stabilization of hypoxia inducible factor-1α by different intracellular sources of reactive oxygen species.
abstract: Intratumoral hypoxia is a major obstacle in the development of effective cancer chemotherapy, decreasing the efficacy of anti-neoplastic drugs in several solid tumours. The hypoxic environment, through its master regulator hypoxia inducible factor-1 (HIF-1), is able to maintain an anti-apoptotic potential through activation of critical genes associated with drug resistance. Besides affecting metabolism and motility of tumour cells, hypoxia also paradoxically increases production of reactive oxygen species (ROS), which contribute to stabilize HIF-1 through a redox-mediated inhibition of its proteolysis. Here we reported that 1% O(2) hypoxia increases the resistance of human metastatic melanoma cells to conventional chemotherapy with etoposide, and that the increase in chemoresistance strongly depends on ROS delivery due to hypoxia. We reported a biphasic redox-dependent role of HIF-1, involving mitochondrial complex III and NADPH oxidase as oxidants sources, synergising in enhancing survival to chemotherapy. The feed-forward loop engaged by hypoxia involves first an HIF-1-dependent vascular endothelial growth factor-A (VEGF-A) autocrine production and, in the later phase, activation of NADPH oxidase from VEGF/VEGFR2 interaction, finally leading to a further redox-dependent long lasting stabilization of HIF-1. We therefore identified a redox-dependent circuitry linking hypoxia-driven ROS to VEGF-A secretion and to enhanced melanoma cell survival to etoposide chemotherapy.
authors.affiliation: Department of Biochemical Sciences, University of Florence, Florence, Italy.
authors.forename: Maura
authors.initials: M
authors.lastname: Calvani
authors.forename: Giuseppina
authors.initials: G
authors.lastname: Comito
authors.forename: Elisa
authors.initials: E
authors.lastname: Giannoni
authors.forename: Paola
authors.initials: P
authors.lastname: Chiarugi
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology; D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D000068258:Bevacizumab; D015153:Blotting, Western; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D014450:Electron Transport Complex III / Q000235:genetics / Q000378:metabolism; D005047:Etoposide / Q000494:pharmacology; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D042541:Intracellular Space / Q000187:drug effects / Q000378:metabolism*; D008545:Melanoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D010084:Oxidation-Reduction / Q000187:drug effects; D055550:Protein Stability; D034622:RNA Interference; D017382:Reactive Oxygen Species / Q000378:metabolism*; D012402:Rotenone / Q000494:pharmacology; D013997:Time Factors; D014475:Uncoupling Agents / Q000494:pharmacology; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology
chemical_list: D020533:Angiogenesis Inhibitors; D061067:Antibodies, Monoclonal, Humanized; D000972:Antineoplastic Agents, Phytogenic; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D017382:Reactive Oxygen Species; C037989:Rieske iron-sulfur protein; D014475:Uncoupling Agents; D042461:Vascular Endothelial Growth Factor A; D012402:Rotenone; D000068258:Bevacizumab; D005047:Etoposide; D006861:Hydrogen Peroxide; D014450:Electron Transport Complex III