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BMC Medicine
Published in: BMC Medicine 1/2009

Open Access 01-12-2009 | Research article

STAT1-dependent expression of energy metabolic pathways links tumour growth and radioresistance to the Warburg effect

Authors: Sean P Pitroda, Bassam T Wakim, Ravi F Sood, Mara G Beveridge, Michael A Beckett, Dhara M MacDermed, Ralph R Weichselbaum, Nikolai N Khodarev

Published in: BMC Medicine | Issue 1/2009

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Abstract

Background

The Signal Transducer and Activator of Transcription 1 (STAT1) has traditionally been regarded as a transmitter of interferon signaling and a pro-apoptotic tumour suppressor. Recent data have identified new functions of STAT1 associated with tumourigenesis and resistance to genotoxic stress, including ionizing radiation (IR) and chemotherapy. To investigate the mechanisms contributing to the tumourigenic functions of STAT1, we performed a combined transcriptomic-proteomic expressional analysis and found that STAT1 is associated with regulation of energy metabolism with potential implication in the Warburg effect.

Methods

We generated a stable knockdown of STAT1 in the SCC61 human squamous cell carcinoma cell line, established tumour xenografts in athymic mice, and compared transcriptomic and proteomic profiles of STAT1 wild-type (WT) and knockdown (KD) untreated or irradiated (IR) tumours. Transcriptional profiling was based on Affymetrix Human GeneChip® Gene 1.0 ST microarrays. Proteomes were determined from the tandem mass spectrometry (MS/MS) data by searching against the human subset of the UniProt database. Data were analysed using Significance Analysis of Microarrays for ribonucleic acid and Visualize software for proteins. Functional analysis was performed with Ingenuity Pathway Analysis with statistical significance measured by Fisher's exact test.

Results

Knockdown of STAT1 led to significant growth suppression in untreated tumours and radio sensitization of irradiated tumours. These changes were accompanied by alterations in the expression of genes and proteins of glycolysis/gluconeogenesis (GG), the citrate cycle (CC) and oxidative phosphorylation (OP). Of these pathways, GG had the most concordant changes in gene and protein expression and demonstrated a STAT1-dependent expression of genes and proteins consistent with tumour-specific glycolysis. In addition, IR drastically suppressed the GG pathway in STAT1 KD tumours without significant change in STAT1 WT tumours.

Conclusion

Our results identify a previously uncharacterized function of STAT1 in tumours: expressional regulation of genes encoding proteins involved in glycolysis, the citrate cycle and mitochondrial oxidative phosphorylation, with predominant regulation of glycolytic genes. STAT1-dependent expressional regulation of glycolysis suggests a potential role for STAT1 as a transcriptional modulator of genes responsible for the Warburg effect.
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Metadata
Title
STAT1-dependent expression of energy metabolic pathways links tumour growth and radioresistance to the Warburg effect
Authors
Sean P Pitroda
Bassam T Wakim
Ravi F Sood
Mara G Beveridge
Michael A Beckett
Dhara M MacDermed
Ralph R Weichselbaum
Nikolai N Khodarev
Publication date
01-12-2009
Publisher
BioMed Central
Published in
BMC Medicine / Issue 1/2009
Electronic ISSN: 1741-7015
DOI
https://doi.org/10.1186/1741-7015-7-68

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