title: A STAT3-mediated metabolic switch is involved in tumour transformation and STAT3 addiction.
abstract: The pro-oncogenic transcription factor STAT3 is constitutively activated in a wide variety of tumours that often become addicted to its activity, but no unifying view of a core function determining this widespread STAT3-dependence has yet emerged. We show here that constitutively active STAT3 acts as a master regulator of cell metabolism, inducing aerobic glycolysis and down-regulating mitochondrial activity both in primary fibroblasts and in STAT3-dependent tumour cell lines. As a result, cells are protected from apoptosis and senescence while becoming highly sensitive to glucose deprivation. We show that enhanced glycolysis is dependent on HIF-1α up-regulation, while reduced mitochondrial activity is HIF-1α-independent and likely caused by STAT3-mediated down-regulation of mitochondrial proteins. The induction of aerobic glycolysis is an important component of STAT3 pro-oncogenic activities, since inhibition of STAT3 tyrosine phosphorylation in the tumour cell lines down-regulates glycolysis prior to leading to growth arrest and cell death, both in vitro and in vivo. We propose that this novel, central metabolic role is at the core of the addiction for STAT3 shown by so many biologically different tumours.
authors.affiliation: Molecular Biotechnology Center and Department of Genetics, Biology and Biochemistry, University of Turin, Via Nizza 52, 10126 Turin, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Demaria
authors.forename: Carlotta
authors.initials: C
authors.lastname: Giorgi
authors.forename: Magdalena
authors.initials: M
authors.lastname: Lebiedzinska
authors.forename: Giovanna
authors.initials: G
authors.lastname: Esposito
authors.forename: Luca
authors.initials: L
authors.lastname: D'Angeli
authors.forename: Antonietta
authors.initials: A
authors.lastname: Bartoli
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Gough
authors.forename: James
authors.initials: J
authors.lastname: Turkson
authors.forename: David E
authors.initials: DE
authors.lastname: Levy
authors.forename: Christine J
authors.initials: CJ
authors.lastname: Watson
authors.forename: Mariusz R
authors.initials: MR
authors.lastname: Wieckowski
authors.forename: Paolo
authors.initials: P
authors.lastname: Provero
authors.forename: Paolo
authors.initials: P
authors.lastname: Pinton
authors.forename: Valeria
authors.initials: V
authors.lastname: Poli
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic; D002478:Cells, Cultured; D004734:Energy Metabolism; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism / Q000502:physiology; D020869:Gene Expression Profiling; D006019:Glycolysis / Q000502:physiology; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D046228:Microarray Analysis; D008928:Mitochondria / Q000378:metabolism; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology
chemical_list: C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D017382:Reactive Oxygen Species; D050796:STAT3 Transcription Factor