Title

STAT3-mediated metabolic switch is involved in tumour transformation and STAT3 addiction

Authors

Authors

M. Demaria; C. Giorgi; M. Lebiedzinska; G. Esposito; L. D'Angeli; A. Bartoli; D. J. Gough; J. Turkson; D. E. Levy; C. J. Watson; M. R. Wieckowski; P. Provero; P. Pinton;V. Poli

Comments

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Abbreviated Journal Title

Aging-US

Keywords

cell metabolism; mitochondria; STAT3; tumours; Warburg effect; HIF-1; alpha; SIGNAL TRANSDUCER; CANCER-CELLS; MITOCHONDRIAL STAT3; EXPRESSION; HYPOXIA; CALCIUM; TARGET; TRANSCRIPTION-3; INFLAMMATION; ACTIVATOR; Cell Biology

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-1a up-regulation, while reduced mitochondrial activity is HIF-1 alpha-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.

Journal Title

Aging-Us

Volume

2

Issue/Number

11

Publication Date

1-1-2010

Document Type

Article

Language

English

First Page

823

Last Page

842

WOS Identifier

WOS:000285693900013

ISSN

1945-4589

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