Regulation of Monocarboxylate Transporter MCT1 Expression by p53 Mediates Inward and Outward Lactate Fluxes in Tumors

Abstract

The monocarboxylate transporter (MCT) family member MCT1 can transport lactate into and out of tumor cells. Whereas 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 p53À/À tumor cells, NF-kB further supported expression of MCT1 to elevate its levels. Following glucose deprivation, upregulated MCT1 in p53 À/À 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 availability. Cancer Res; 72(4); 939-48. Ó2011 AACR.

Glucose deprivation increases monocarboxylate transporter 1 (MCT1) expression and MCT1-dependent tumor cell migration

“…As CD147 beyond MCT1 associates with a number of partners (including MCT4) to form supercomplexes, 39 additional and perhaps more indirect influences cannot be excluded. Furthermore, additional controls would be involved under hypoxia, [40][41][42] explaining why hypoxia can fail to induce or can even repress MCT1 expression in vivo 3,43 whereas it stimulates MCT1 expression in vitro 44 (Figure 2a), and why we detected increased MCT1 expression at early time points (Figure 2a, 24 h) whereas others did not find MCT1 induction upon a longer exposure to hypoxia (48 h). 5 Modulating ROS can indeed impact the response of MCT1 to hypoxia (Supplementary Figure 4A).…”

Reciprocal Metabolic Reprogramming through Lactate Shuttle Coordinately Influences Tumor-Stroma Interplay

“…Hypoxic and normoxic areas of tumors are able to engage a sort of Cori Cycle culminating in fueling respiration of normoxic cells with lactate at expenses of the anaerobic metabolism of hypoxic cells (12). In addition, MCT1 expression and lactate upload has been correlated with p53 loss, with higher MCT1 expressed by tumors associated with poorer clinical outcome (37). In keeping with these data, we show here that MCT1 expression by PCa is mandatory for tumor outgrowth, as indicated by the efficiency of in vivo targeting of MCT1 with CHC or RNA interference.…”

Glutamine Deprivation Enhances Antitumor Activity of 3-Bromopyruvate through the Stabilization of Monocarboxylate Transporter-1

“…According to the "stromal-epithelial" lactate shuttle in tumors, MCT-1 allows the uptake of lactate, ketones, and other metabolites released by stromal fibroblasts in the extracellular milieu to refuel epithelial cancer cells within the same tumors (46). Interestingly, although MCT-1 expression is affected by hypoxia (48), no data documenting its modulation in response to nutrient availability had been provided so far. Although we did not investigate the role of MCT-1 upregulation in glutamine-deprived cells, at least one hypothesis can be formulated.…”