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Aging (Albany NY). 2010 Nov;2(11):823-42.

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

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1
Molecular Biotechnology Center and Department of Genetics, Biology and Biochemistry, University of Turin, Via Nizza 52, 10126 Turin, Italy.

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.

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PMID:
21084727
PMCID:
PMC3006025
DOI:
10.18632/aging.100232
[Indexed for MEDLINE]
Free PMC Article
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