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.

Bayesian Learning from Marginal Data in Bionetwork Models

“…A signature defined as a biologically descriptive and predictive set of numerical summaries of a higher-dimensional phenotype is wellestablished (e.g. Huang et al, 2003, Lucas et al, 2009, Chen et al, 2010 and inspired the ideas proposed here. The construction of signatures using a biologically relevant spectrum of reference distributions, coupled with the obvious formal statistical placement of a new data set on that spectrum via equation (7), is specific to the marginal data context though may well be more broadly relevant in other areas in future.…”

Tumor cell metabolism

“…49 Acidosis drives a stress response in tumor cells by provoking cell cycle arrest, restricting ribosomal biogenesis (the most energy demanding cellular process) and increasing mitochondrial activity. 50,51 As a result, tumor cells undergo cycles of cellular quiescence and proliferation, depending on nutrient concentrations and pH 52 ( Fig. 2).…”

“…This phenomenon may be mediated by the suppression of the Akt and HIF-1 pathways. 26,51 Acidosis has also been shown to stimulate inflammatory cells, such as neutrophils and dendritic cells; this inflammatory response is mediated via PI3K/Akt activation. 58 More studies are needed to elucidate the participation of Akt and HIF-1 in tumor cell survival under acidic conditions, while taking lactate concentration, hypoxia, normoxia and timing into account.…”

Coordination of Nutrient Availability and Utilization by MAX- and MLX-Centered Transcription Networks

“…First, TXNIP levels are reduced or not detectable in MondoA knockdown or knockout cells grown in glucose-containing medium. Similarly, glucose induction of TXNIP is reduced or eliminated in MondoA knockdown or knockout cells (Stoltzman et al 2008(Stoltzman et al , 2011Kaadige et al 2009;Chen et al 2010a;Peterson et al 2010). Thus, MondoA is required for TXNIP expression under basal glucose conditions and glucose induction.…”

“…In collaboration with the Chi group, we showed that the LAinduced increase in TXNIP was entirely dependent on MondoA and glucose. Further, we used chromatin immunoprecipitation (ChIP) to show that MondoA occupies the TXNIP promoter more robustly under LA growth conditions (Chen et al 2010a). This finding suggests that LA controls either the amount of MondoA in the nucleus or the DNA-binding activity of MondoA:MLX complexes, rather than controlling the transcriptional activity of MondoA: MLX complexes.…”