The Plasma Membrane Lactate Transporter MCT4, but Not MCT1, Is Up-regulated by Hypoxia through a HIF-1α-dependent Mechanism*

By M. S. Ullah, A. Davies, A. Halestrap. Journal of Biological Chemistry, 2006

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The monocarboxylate transporter MCT4 mediates lactic acid efflux from most tissues that are dependent on glycolysis for their ATP production. Here we demonstrate that expression of MCT4 mRNA and protein was increased >3-fold by a 48-h exposure to 1% O2, whereas MCT1 expression was not increased. The effect was mimicked by CoCl2 (50 μm), suggesting transcriptional regulation by hypoxia-inducible factor 1α (HIF-1α). The predicted promoters for human MCT1, MCT2, and MCT4 were cloned into the pGL3 vector and shown to be active (luciferase luminescence) under basal conditions. Only the MCT4 promoter was activated (>2-fold) by hypoxia. No response was found in cells lacking HIF-1α. Four potential hypoxia-response elements were identified, but deletion analysis implicated only two in the hypoxia response. These were just upstream from the transcription start site and also found in the mouse MCT4 promoter. Mutation of site 2 totally abolished the hypoxic response, whereas mutation of site 1 only reduced the response. Gel-shift analysis demonstrated that nuclear extracts of hypoxic but not normoxic HeLa cells contained two transcription factors that bound to DNA probes containing these hypoxia-response elements. The major shifted band was abolished by mutation of site 2, and supershift analysis confirmed that HIF-1α bound to this site. Binding of the second factor was abolished by mutation of site 1. We conclude that MCT4, like other glycolytic enzymes, is up-regulated by hypoxia through a HIF-1α-mediated mechanism. This adaptive response allows the increased lactic acid produced during hypoxia to be rapidly lost from the cell.

Subfields: Cancer Research, Molecular Biology, Physiology

View Paper: https://www.semanticscholar.org/paper/9a0754dc357d98cc77573e3bd33c5086bb4b9b49

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Citations in the corpus

Regulation of glycolysis by the hypoxia‐inducible factor (HIF): implications for cellular physiology (2020, background): “…activated neutrophils and classically activated macrophages, glycolysis is crucial to support their infiltrating capacity and microbicidal actions (Valentine & Beck, 1951; Sbarra & Karnovsky, 1959), such that inhibition of glycolysis with 2-DG prevents macrophage activation and inhibits…”
Hypoxia and cancer (2007, background): “Among these are the growth factor activatable and amiloride-sensitive Na+/H+ Exchanger (NHE-1) [32–34] and the H+/lactate cotransporter (monocarboxylate transporter, MCT1 and MCT4) [35].”
Tumour hypoxia induces a metabolic shift causing acidosis: a common feature in cancer (2009, background): “Moreover, in a low oxygen environment, hypoxic tumour cells develop supplemental key pHi-regulating systems such as MCT4 [22] and the membrane-associated carbonic anhydrases (CAs, EC: 4.”
Activity‐dependent regulation of energy metabolism by astrocytes: An update (2007, background): “Overexpression was also observed for MCT1 but not for GLUT1 under inflammatory conditions, and for MCT4 under hypoxia (Ullah et al., 2006), providing a more rapid release of lactate that might contribute to a protective mechanism for neurons.”
Hypoxia, HIF1 and glucose metabolism in the solid tumour (2008, background): “The lactate can then be removed from the cell through the action of the HIF-inducible plasma membrane monocarboxylate transporter 4 (MCT4, SLC16A4”
Lactate in the Regulation of Tumor Microenvironment and Therapeutic Approaches (2019, background): “On the other hand, MCT4 (SLC16A3) is expressed strongly in glycolytic tissue (114) and has low affinity for lactate (25–30mM) and it does not import serum lactate (<2mM) (115).”
Targeting lactate-fueled respiration selectively kills hypoxic tumor cells in mice. (2008, background): “5–10 mM) and is predominantly found at the plasma membrane of oxidative muscle fibers, where it promotes lactate influx and oxidation (13, 16, 32).”
Interfering with pH regulation in tumours as a therapeutic strategy (2011, background): “Indeed, MCTs are overexpressed in many tumours, with MCT4 also being induced by hypoxia through HIF1 signalling, although this remains a controversial issu”