title: Leptin contributes to long-term stabilization of HIF-1α in cancer cells subjected to oxygen limiting conditions.
abstract: Leptin, a cytokine produced by the adipose tissue in response to food intake, is a key player in the regulation of energy balance and body weight control. Physiological action of leptin in modulating the metabolic adaptation of different peripheral tissues supports the hypothesis that it could also exert a direct effect on cancer cells. In vitro, treatment with leptin up-regulated HIF-1α and stimulated adhesion and invasion of prostate cancer cells cultured in hypoxia. Leptin action was effective in both low and high glycolytic cancer cell lines, and determined the up-regulation of lactate exporter MCT4 and its associated protein CD147. HIF-1α stabilization was oligomycin-independent and was associated with an important modulation of mitochondrial homeostasis. In fact, leptin treatment produced mitochondrial biogenesis, stabilization of mitochondrial membrane potential and increased uncoupled respiration through the up-regulation of UCP2. Furthermore, leptin counteracted the downmodulation of SIRT1 induced by hypoxia, and persistent high levels of SIRT1 were directly involved in HIF-1α stabilization. Leptin can sustain cancer progression in hypoxic environment and when mitochondrial respiration is impaired. Leptin signaling axis, including the new proposed intermediate SIRT1, could represent a new diagnostic and therapeutic target in prostate cancer.
authors.affiliation: Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, 67100 L'Aquila, Italy.
authors.forename: Alessia
authors.initials: A
authors.lastname: Calgani
authors.affiliation: Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, 67100 L'Aquila, Italy.
authors.forename: Simona
authors.initials: S
authors.lastname: Delle Monache
authors.affiliation: Department of Life, Health and Environmental Sciences, University of L'Aquila, 67100 L'Aquila, Italy.
authors.forename: Patrizia
authors.initials: P
authors.lastname: Cesare
authors.affiliation: Department of Life, Health and Environmental Sciences, University of L'Aquila, 67100 L'Aquila, Italy.
authors.forename: Carlo
authors.initials: C
authors.lastname: Vicentini
authors.affiliation: Department of Life, Health and Environmental Sciences, University of L'Aquila, 67100 L'Aquila, Italy.
authors.forename: Mauro
authors.initials: M
authors.lastname: Bologna
authors.affiliation: Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, 67100 L'Aquila, Italy. Electronic address: adriano.angelucci@univaq.it.
authors.forename: Adriano
authors.initials: A
authors.lastname: Angelucci
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism* / Q000556:secondary; D000368:Aged; D051926:Basigin / Q000235:genetics / Q000378:metabolism; D002448:Cell Adhesion / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D020738:Leptin / Q000494:pharmacology*; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008875:Middle Aged; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D027501:Monocarboxylic Acid Transporters / Q000235:genetics / Q000378:metabolism; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism; D009361:Neoplasm Invasiveness; D001678:Organelle Biogenesis; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D055550:Protein Stability; D034622:RNA Interference; D056564:Sirtuin 1 / Q000235:genetics / Q000378:metabolism; D013997:Time Factors; D014162:Transfection; D000072258:Tumor Hypoxia; D059016:Tumor Microenvironment; D000071246:Uncoupling Protein 2 / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation
chemical_list: C497886:BSG protein, human; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D020738:Leptin; D027501:Monocarboxylic Acid Transporters; D009124:Muscle Proteins; C406962:SLC16A4 protein, human; C000604389:UCP2 protein, human; D000071246:Uncoupling Protein 2; D051926:Basigin; C447939:SIRT1 protein, human; D056564:Sirtuin 1
keywords: Mitochondria; Obesity; SIRT1; UCP2; Uncoupled respiration