Leptin contributes to long-term stabilization of HIF-1α in cancer cells subjected to oxygen limiting conditions. Issue 1 (28th June 2016)

• Record Type: Journal Article
• Authors: Calgani, Alessia; Delle Monache, Simona; Cesare, Patrizia; Vicentini, Carlo; Bologna, Mauro; Angelucci, Adriano
• Is Part Of: Cancer letters. Volume 376:Issue 1(2016)
• Page Start: 1
• Page End: 9
• Publication Date: 2016-06-28
• Subjects: Obesity -- Mitochondria -- Uncoupled respiration -- UCP2 -- SIRT1; Cancer -- Periodicals; Neoplasms -- Periodicals; Cancer -- Périodiques; Electronic journals; 616.994
• DOI: 10.1016/j.canlet.2016.03.027
• Languages: English
• ISSNs: 0304-3835

Abstract

Highlights: Leptin up-regulates HIF-1α and stimulates adhesion and invasion of cancer cells cultured in hypoxia. Leptin stabilizes mitochondrial membrane potential and increases uncoupled respiration. Leptin counteracts the downmodulation of SIRT1 induced by hypoxia. Persistent high levels of SIRT1 are directly involved in HIF-1α stabilization. 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.