PMID- 19891767
OWN - NLM
STAT- MEDLINE
DCOM- 20091217
LR  - 20220408
IS  - 1741-7015 (Electronic)
IS  - 1741-7015 (Linking)
VI  - 7
DP  - 2009 Nov 5
TI  - STAT1-dependent expression of energy metabolic pathways links tumour growth and 
      radioresistance to the Warburg effect.
PG  - 68
LID - 10.1186/1741-7015-7-68 [doi]
AB  - 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(R) 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.
FAU - Pitroda, Sean P
AU  - Pitroda SP
AD  - Department of Radiation and Cellular Oncology, The University of Chicago, 
      Chicago, IL 60637, USA. spitroda@uchicago.edu
FAU - Wakim, Bassam T
AU  - Wakim BT
FAU - Sood, Ravi F
AU  - Sood RF
FAU - Beveridge, Mara G
AU  - Beveridge MG
FAU - Beckett, Michael A
AU  - Beckett MA
FAU - MacDermed, Dhara M
AU  - MacDermed DM
FAU - Weichselbaum, Ralph R
AU  - Weichselbaum RR
FAU - Khodarev, Nikolai N
AU  - Khodarev NN
LA  - eng
GR  - CA071933/CA/NCI NIH HHS/United States
GR  - CA111423/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20091105
PL  - England
TA  - BMC Med
JT  - BMC medicine
JID - 101190723
RN  - 0 (Proteome)
RN  - 0 (STAT1 Transcription Factor)
RN  - 0 (STAT1 protein, human)
SB  - IM
MH  - Animals
MH  - Cell Line, Tumor
MH  - *Energy Metabolism
MH  - Gene Expression Profiling
MH  - *Gene Expression Regulation, Neoplastic
MH  - Gene Knockdown Techniques
MH  - Humans
MH  - Metabolic Networks and Pathways/*genetics
MH  - Mice
MH  - Neoplasms/drug therapy/*radiotherapy
MH  - Oligonucleotide Array Sequence Analysis
MH  - Proteome/analysis
MH  - *Radiation Tolerance
MH  - STAT1 Transcription Factor/genetics/*metabolism
MH  - Tandem Mass Spectrometry
PMC - PMC2780454
EDAT- 2009/11/07 06:00
MHDA- 2009/12/18 06:00
PMCR- 2009/11/05
CRDT- 2009/11/07 06:00
PHST- 2009/10/02 00:00 [received]
PHST- 2009/11/05 00:00 [accepted]
PHST- 2009/11/07 06:00 [entrez]
PHST- 2009/11/07 06:00 [pubmed]
PHST- 2009/12/18 06:00 [medline]
PHST- 2009/11/05 00:00 [pmc-release]
AID - 1741-7015-7-68 [pii]
AID - 10.1186/1741-7015-7-68 [doi]
PST - epublish
SO  - BMC Med. 2009 Nov 5;7:68. doi: 10.1186/1741-7015-7-68.