Abstract 2340: Lactic acidosis triggers starvation response with distinct metabolic profiles by the induction of TXNIP through MondoA

Abstract

Although lactic acidosis and other tumor microenvironmental stresses are prominent features in solid tumors, how they influence the phenotypes of cancer cells are not well understood. We compared the transcriptional response of breast cancer cells under three distinct tumor microenvironmental stresses – lactic acidosis, glucose deprivation and hypoxia. We found that lactic acidosis induced gene expression highly similar to glucose deprivation and triggered features of starvation response. In spite of their similar transcriptional response, lactic acidosis had opposite effects on the glucose uptake to glucose deprivation. This discrepancy guided the supervised analysis of expression data to identify TXNIP as the potential regulator for such divergent metabolic effects. TXNIP and its paralogue ARRDC4 were both induced under lactic acidosis and repressed with glucose deprivation. Their expression was also highly correlated with predicted lactic acidosis pathway activities and associated with favorable clinical outcomes in human cancers. These findings are due to the ability of TXNIP to inhibit the tumor glycolytic phenotypes and redirect energy generation toward aerobic respiration. The induction of TXNIP under lactic acidosis is caused by the activation of the glucose-sensing helix-loop-helix transcriptional complex MondoA: Mlx. Lactic acidosis activates the MondoA-TXNIP pathways and contributes to its “anti-Warburg” metabolic effects and anti-tumor properties of cancer cells. These findings illustrate the value of such integrative analysis of transcriptome and metabolic response under various tumor microenvironmental stresses and may lead to important insights on how they influence the phenotypic and metabolic adaptations in human cancers. 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 2340.