{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nMonocarboxylate transporters (MCTs) form a family of plasma‐membrane proteins that mediate the bidirectional transport of lactate, pyruvate and other monocarboxylates, thereby regulating intracellular pH and sustaining glycolytic metabolism. In rapidly proliferating and hypoxic cells – including many tumor types – hypoxia‐inducible factor‐1α (HIF‑1α) drives the transcriptional upregulation of certain isoforms (for example, MCT4), facilitating the efflux of lactate produced during glycolysis and establishing a lactate shuttle between glycolytic stromal cells and oxidative cancer cells. These studies emphasize that robust expression of lactate transporters is a key adaptive response, coupling metabolic pathways and ensuring cellular energy balance in both normal and malignant tissues."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "14"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nExtensive investigation in diverse cancer types reveals that differential expression of MCT isoforms is closely associated with tumor aggressiveness, invasion, metastasis and resistance to therapy. In many malignancies, elevated MCT4 expression marks highly glycolytic, hypoxic regions – often in tumor stroma – while MCT1 is predominantly expressed in oxidative, proliferative cancer cells, mediating lactate uptake. Such metabolic compartmentalization supports the “reverse Warburg effect” and overall tumor metabolic symbiosis. Functional studies show that inhibition or knockdown of these transporters hampers lactate flux, disrupts intracellular pH regulation, and eventually impairs cell proliferation and invasion; these observations underscore the potential of targeting lactate transport to counteract tumor progression."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "15", "end_ref": "26"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nWithin the SLC16 gene family, however, not all isoforms contribute equally to these processes. SLC16A4 – which encodes MCT5 – appears to have a more limited or distinct role compared with the well‐characterized MCT1 and MCT4. For instance, while many studies demonstrate that robust lactate transport via MCT1 and MCT4 is critical for maintaining glycolytic flux, pH homeostasis and even promoting cancer cell invasiveness, direct functional associations for SLC16A4 (MCT5) have not been substantiated; one study specifically noted that MCT5 expression did not correlate with cancer cell invasion. This suggests that whereas the bulk of tumor metabolism regulation can be attributed to isoforms such as MCT1 and MCT4, SLC16A4 may play a subordinate or context‐dependent role in lactate handling. Collectively, these data indicate that although SLC16A4 belongs to the same transporter family, its function in supporting the energetic and survival demands of highly metabolic tissues – including in malignant settings – remains relatively modest, thereby distinguishing it from its counterparts in the orchestration of the metabolic adaptations seen in tumors."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "27", "end_ref": "41"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Mohammed S Ullah, Andrew J Davies, Andrew P Halestrap "}, {"type": "b", "children": [{"type": "t", "text": "The plasma membrane lactate transporter MCT4, but not MCT1, is up-regulated by hypoxia through a HIF-1alpha-dependent mechanism."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2006)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M511397200"}], "href": "https://doi.org/10.1074/jbc.M511397200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "16452478"}], "href": "https://pubmed.ncbi.nlm.nih.gov/16452478"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Renaud Le Floch, Johanna Chiche, Ibtissam Marchiq, et al. 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