Lactic acidosis triggers starvation response with paradoxical induction of TXNIP through MondoA.
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Although lactic acidosis is a prominent feature of solid tumors, we still have limited understanding of the mechanisms by which lactic acidosis influences metabolic phenotypes of cancer cells. We compared global transcriptional responses of breast cancer cells in response to three distinct tumor microenvironmental stresses: lactic acidosis, glucose deprivation, and hypoxia. We found that lactic acidosis and glucose deprivation trigger highly similar transcriptional responses, each inducing features of starvation response. In contrast to their comparable effects on gene expression, lactic acidosis and glucose deprivation have opposing effects on glucose uptake. This divergence of metabolic responses in the context of highly similar transcriptional responses allows the identification of a small subset of genes that are regulated in opposite directions by these two conditions. Among these selected genes, TXNIP and its paralogue ARRDC4 are both induced under lactic acidosis and repressed with glucose deprivation. This induction of TXNIP under lactic acidosis is caused by the activation of the glucose-sensing helix-loop-helix transcriptional complex MondoA:Mlx, which is usually triggered upon glucose exposure. Therefore, the upregulation of TXNIP significantly contributes to inhibition of tumor glycolytic phenotypes under lactic acidosis. Expression levels of TXNIP and ARRDC4 in human cancers are also highly correlated with predicted lactic acidosis pathway activities and associated with favorable clinical outcomes. Lactic acidosis triggers features of starvation response while activating the glucose-sensing MondoA-TXNIP pathways and contributing to the "anti-Warburg" metabolic effects and anti-tumor properties of cancer cells. These results stem from integrative analysis of transcriptome and metabolic response data under various tumor microenvironmental stresses and open new paths to explore how these stresses influence phenotypic and metabolic adaptations in human cancers.
Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
Cell Line, Tumor
Metabolic Networks and Pathways
Published Version (Please cite this version)10.1371/journal.pgen.1001093
Publication InfoChen, Julia Ling-Yu; Merl, Daniel; Peterson, Christopher W; Wu, Jianli; Liu, Patrick Yantyng; Yin, Hanwei; ... Chi, Jen-Tsan (2010). Lactic acidosis triggers starvation response with paradoxical induction of TXNIP through MondoA. PLoS Genet, 6(9). pp. e1001093. 10.1371/journal.pgen.1001093. Retrieved from https://hdl.handle.net/10161/4477.
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Associate Professor in Molecular Genetics and Microbiology
We are using functional genomic approaches to investigate the nutrient signaling and stress adaptations of cancer cells when exposed to various nutrient deprivations and microenvironmental stress conditions. Recently, we focus on two areas. First, we are elucidating the genetic determinants and disease relevance of ferroptosis, a newly recognized form of cell death. Second, we have identified the mammalian stringent response pathway which is highly similar to bacterial stringent response, but
Professor of Medicine
Deb Muoio is a Professor of Medicine, Division of Endocrinology, and Director of Basic Research at the Duke Molecular Physiology Institute. She earned a PhD in Nutritional Biochemistry at the University of North Carolina, Chapel Hill, followed by postdoctoral fellowships at East Carolina and Duke Universities working in the areas of muscle physiology and metabolic disease. Her laboratory studies mechanisms of metabolic control and molecular events that link nutrition and exercise to health ou
Arts and Sciences Distinguished Professor of Statistics and Decision Sciences
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