Regulation of Monocarboxylate Transporter MCT1 Expression by p53 Mediates Inward and Outward Lactate Fluxes in Tumors
- 14 February 2012
- journal article
- Published by American Association for Cancer Research (AACR) in Cancer Research
- Vol. 72 (4), 939-948
- https://doi.org/10.1158/0008-5472.can-11-2474
Abstract
The monocarboxylate transporter MCT family member MCT1 can transport lactate into and out of tumor cells. While most oxidative cancer cells import lactate through MCT1 to fuel mitochondrial respiration, the role of MCT1 in glycolysis-derived lactate efflux remains less clear. In this study we identified a direct link between p53 function and MCT1 expression. Under hypoxic conditions, p53 loss promoted MCT1 expression and lactate export produced by elevated glycolytic flux, both in vitro and in vivo. p53 interacted directly with the MCT1 gene promoter and altered MCT1 mRNA stabilization. In hypoxic p53-/- tumor cells, NF-κB further supported expression of MCT1 to elevate its levels. Following glucose deprivation, upregulated MCT1 in p53-/- cells promoted lactate import and favored cell proliferation by fuelling mitochondrial respiration. We also found that MCT1 expression was increased in human breast tumors harboring p53 mutations and coincident features of hypoxia, with higher MCT1 levels associated with poorer clinical outcomes. Together, our findings identify MCT1 as a target for p53 repression and they suggest that MCT1 elevation in p53-deficient tumors allows them to adapt to metabolic needs by facilitating lactate export or import depending on the glucose availabilityKeywords
Other Versions
This publication has 38 references indexed in Scilit:
- Lactate shuttles at a glance: from physiological paradigms to anti-cancer treatmentsDisease Models & Mechanisms, 2011
- Astrocyte-Neuron Lactate Transport Is Required for Long-Term Memory FormationCell, 2011
- The Spatial Organization of Proton and Lactate Transport in a Rat Brain TumorPLOS ONE, 2011
- The shunt problem: control of functional shunting in normal and tumour vasculatureNature Reviews Cancer, 2010
- Tumor Metabolism of Lactate: The Influence and Therapeutic Potential for MCT and CD147 RegulationFuture Oncology, 2009
- Cell–cell and intracellular lactate shuttlesThe Journal of Physiology, 2009
- Understanding the Warburg Effect: The Metabolic Requirements of Cell ProliferationScience, 2009
- Tumor suppressors and cell metabolism: a recipe for cancer growthGenes & Development, 2009
- Association of p53 gene alterations with the expression of antiapoptotic survivin splice variants in breast cancerOncogene, 2006
- Genome-Wide Analysis of p53 under Hypoxic ConditionsMolecular and Cellular Biology, 2006