Abstract 44: STAT1-dependent expression of genes and proteins involved in energy metabolism links tumor growth and radioresistance to the Warburg effect and predicts poor prognosis in cancer patients

Abstract

Abstract Signal Transducer and Activator of Transcription 1 (STAT1) has traditionally been regarded as a transmitter of interferon signaling and a pro-apoptotic tumor suppressor. Recent data have identified new functions of STAT1 associated with tumorigenesis and resistance to genotoxic stress, including ionizing radiation (IR) and chemotherapy. To investigate the mechanisms contributing to the tumorigenic functions of STAT1, we performed a combined transcriptomic-proteomic expressional analysis of tumor xenografts with stable Stat1 knock-down (KD) relative to tumors with wild type (wt) Stat1. We also compared previously described SCC61 and nu61 isologous tumors, where SCC61 is radiosensitive and nu61 is radioresistant counterparts with different expression of IFN/Stat1 pathway. Transcriptional profiling was based on Affymetrix Human GeneChip® Gene 1.0 ST microarrays. Proteomes were determined from the MS/MS data by searching against the human subset of the UniProt database. Knockdown of STAT1 led to significant growth suppression in untreated tumors and radiosensitization of irradiated tumors. 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 tumor-specific glycolysis. IR drastically suppressed the GG pathway in STAT1 KD tumors without significant change in STAT1 WT tumors. Using 18F-FDG-PET we observed significantly higher glucose uptake in nu61 compared to SCC61 post-irradiation (6Gy). The STAT1 and glycolytic pathways were co-expressed in human breast tumors, and expression of STAT1-linked glycolytic genes was highly predictive of poor prognosis. Our results identify a previously uncharacterized function of STAT1 in tumors: expressional regulation of genes and enzymes involved in glycolysis, the citrate cycle, and mitochondrial oxidative phosphorylation, with predominant regulation of glycolysis. STAT1-dependent transcriptional and translational regulation of glycolysis suggests a potential role for STAT1 as a transcriptional modulator of genes responsible for the Warburg effect. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 44.