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

Abstract

BackgroundThe 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.MethodsWe 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.ResultsKnockdown 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.ConclusionOur 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.

Fructose-bisphosphate aldolase A is a key regulator of hypoxic adaptation in colorectal cancer cells and involved in treatment resistance and poor prognosis

“…Other studies have reported that the glycolytic pathway and the expression of glycolytic enzymes are associated with cancer radiosensitivity (26,27). We showed that ALDOA expression is positively correlated with the activity of glycolysis, with cell cycle progression and with ROS production.…”

Molecular Pathways: Interferon/Stat1 Pathway: Role in the Tumor Resistance to Genotoxic Stress and Aggressive Growth

“…Concurrently, overexpression of STAT1 led to the upregulation of IRDS genes (16). Stable knock-down of STAT1 led to the radiosensitization of SCC61 and nu61 tumors and downregulation of genes in the IRDS (16,17,20). Consistent with these results, suppression of STAT1 by fludarabine led to the radiosensitization of renal cell carcinoma cell lines (21).…”

Cancer upregulated gene 2, a novel oncogene, enhances migration and drug resistance of colon cancer cells via STAT1 activation

“…These changes were accompanied by alternative patterns of gene expression such as glycolysis/gluconeogenesis, the citric acid cycle, and oxidative phosphorylation. In particular, STAT1 expression had the most significant influence on the glycolysis/gluconeogenesis pathway, suggesting that STAT1-dependent expression of the energy metabolic pathway is associated with tumor growth and resistance to stress such as irradiation (22). We will therefore investigate metabolic pathways such as glycolysis/gluconeogeneis, the citric acid cycle, and oxidative phosphorylation in both Colon26L5-CUG2-shSTAT1 and Colon26L5-CUG2-shCon cells using microarrays in our next study.…”