title: Lactic acidosis triggers starvation response with paradoxical induction of TXNIP through MondoA.
abstract: 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.
authors.affiliation: Institute for Genome Sciences and Policy, Duke University, Durham, North Carolina, United States of America.
authors.forename: Julia Ling-Yu
authors.initials: JL
authors.lastname: Chen
authors.forename: Daniel
authors.initials: D
authors.lastname: Merl
authors.forename: Christopher W
authors.initials: CW
authors.lastname: Peterson
authors.forename: Jianli
authors.initials: J
authors.lastname: Wu
authors.forename: Patrick Yantyng
authors.initials: PY
authors.lastname: Liu
authors.forename: Hanwei
authors.initials: H
authors.lastname: Yin
authors.forename: Deborah M
authors.initials: DM
authors.lastname: Muoio
authors.forename: Don E
authors.initials: DE
authors.lastname: Ayer
authors.forename: Mike
authors.initials: M
authors.lastname: West
authors.forename: Jen-Tsan
authors.initials: JT
authors.lastname: Chi
mesh_terms: D000140:Acidosis, Lactic / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000378:metabolism*; D002352:Carrier Proteins / Q000378:metabolism*; D045744:Cell Line, Tumor; D005947:Glucose / Q000172:deficiency* / Q000378:metabolism; D006801:Humans; D053858:Metabolic Networks and Pathways / Q000235:genetics; D051379:Mice; D013879:Thioredoxins / Q000378:metabolism*; D013997:Time Factors; D014158:Transcription, Genetic
chemical_list: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D002352:Carrier Proteins; C403128:MLX protein, human; C485496:MLXIP protein, human; C550079:MondoA protein, mouse; C486715:TXNIP protein, human; C445672:Txnip protein, mouse; D013879:Thioredoxins; D005947:Glucose