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Response to Acidity: The MondoA–TXNIP Checkpoint Couples the Acidic Tumor Microenvironment to Cell Metabolism

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Molecular Genetics of Dysregulated pH Homeostasis

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Abstract

Cancer cells reprogram their metabolism toward aerobic glycolysis, which produces lactate to generate an acidic microenvironment. Acidosis-driven activation of the MondoA transcription factor results in its activation of thioredoxin-interacting protein (TXNIP), which is a potent repressor of aerobic glycolysis. We propose a checkpoint function for the MondoA–TXNIP axis that normalizes glycolytic flux in response to a low pH microenvironment.

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Abbreviations

α-KG:

α-ketoglutarate

AMPK:

AMP-activated protein kinase

AOA:

aminooxyacetate

ARRDC4:

arrestin domain containing 4

B-ALL:

B cell acute lymphoblastic leukemia

bHLHZip:

basic helix-loop-helix leucine zipper

ChREBP:

carbohydrate-response element-binding protein

DCD:

dimerization and cytoplasmic localization domain

ECM:

extracellular matrix

G6P:

glucose 6-phosphate

GPCR:

G protein-coupled receptor

GRE:

glucocorticoid response element

HDAC:

histone deacetylase

HIF-1:

hypoxia-inducible factor 1

HMECs:

human mammary epithelial cells

LA:

lactic acidosis

LDHA:

lactate dehydrogenase A

MCR:

mondo conserved region

MCT:

monocarboxylate/H+ cotransporter

MEFs:

murine embryonic fibroblasts

Mlx:

max-like-protein X

mTORC1:

mammalian target of rapamycin complex 1

NES:

nuclear export signal

NHE:

Na+/H+ exchanger

OMM:

outer membrane of the mitochondria

OXPHOS:

oxidative phosphorylation

PFK1:

prosphofructokinase 1

PHD2:

prolyl hydroxylase domain 2

pHe:

extracellular pH

pHi:

intracellular pH

ROS:

reactive oxygen species

TAD:

transcriptional activation domain

TCA:

tricarboxylic acid

TME:

Tumor Microenvironment

TXNIP:

thioredoxin-interacting protein

v-ATPase:

vacuolar-type H+-ATPase

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Acknowledgments

We thank members of the Ayer lab for their insights. R01GM055668-15, R01DK084425-04, and funds from the Huntsman Cancer Foundation support the work in our lab. The Cancer Center Support Grant P30 CA42014 supports core facility use at the Huntsman Cancer Institute.

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  1. Huntsman Cancer Institute, Department of Oncological Sciences, University of Utah, 2000 Circle of Hope, 84112-5550, Salt Lake City, UT, USA

    Zhizhou Ye & Donald E. Ayer

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  1. Zhizhou Ye
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  2. Donald E. Ayer
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Correspondence to Donald E. Ayer .

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  1. Department of Molecular Genetics and Microbiology, Duke Center for Genomic and Computational Biology, Durham, North Carolina, USA

    Jen-Tsan Ashley Chi

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Ye, Z., Ayer, D. (2014). Response to Acidity: The MondoA–TXNIP Checkpoint Couples the Acidic Tumor Microenvironment to Cell Metabolism. In: Chi, JT. (eds) Molecular Genetics of Dysregulated pH Homeostasis. Springer, New York, NY. https://doi.org/10.1007/978-1-4939-1683-2_5

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