2.A.1.13.1
The low affinity proton-linked monocarboxylate (lactate, pyruvate, mevalonate, branched chain oxo acids, β-hydroxybutyrate, γ-hydroxybutyrate, butyrate, acetoacetate, acetate and formate, succinate) uptake/efflux porter (Moschen et al. 2012; Reddy et al. 2020). pH-gated succinate secretion regulates muscle remodeling in response to exercise (Reddy et al. 2020). The structural basis of MCT1 inhibition by anti-cancer drugs has been considered (Wang et al. 2020). MCT1 also transports anti-tumor alkylating agents, 3-bromopyruvate and dichloroacetate (Cooper et al. 1989; Su et al. 2016; Bailey et al. 2019) as well as artemisinin (Girardi et al. 2020). Activity is stimulated by direct interaction with carbonic anhydrase isoform II (Becker et al., 2005). This transporter interacts physically with the chaperone protein Basigin (CD147; TC #8.A.23.1.1) which is required both for targetting to the plasma membrane and for activity. Mct-2 uses a different chaperone protein, GP70. Mct-1 also transports the methionine hydroxy analogue 2-hydroxy (4-methylthio) butanate (Martin-Venegas et al., 2007; Becker and Deitmer, 2008). MCT1, 3 and 4 require the ancillary protein, basigin (P35613; 8.A.23.1.1) for plasma membrane localization (Ovens et al., 2010).  It partially localizes to the peroxysomal membrane (Visser et al. 2007). MCT1 is regulated by CD147 proteins, and this association is important for lactate export and cell proliferation in certain cancer cells (Walters et al. 2013).  It is upregulated in some cancers and maintains the metabolic phenotype of these cancer cells by mediating lactate efflux together with a proton, promoting pH homeostasis (Baltazar et al. 2014). MCT-1 functions as a positive regulator of osteoblast differentiation via suppression of p53 (Sasa et al. 2018). It plays a role in aggressive breast cancer subtypes (Li et al. 2018) as well as other cancers (Park et al. 2018).  The SLC16A1 gene is a potential marker to predict race performance in Arabian horses (Ropka-Molik et al. 2019). MCT1 is a negative regulator and MCT2 and a positive regulator of osteoclast differentiation, while MCT2 is required for bone resorption by osteoclasts (Imai et al. 2019). MCTs 1 and 4 are present in increased amounts in solid tumors, and inhibitors as potential therapeutics have been reviewed (Puri and Juvale 2020). Interleukin-1beta induces monocarboxylate transporter-1 in an oxygen tension-dependent manner (Tanaka et al. 2022). Substrate protonation is a pivotal step in the mechanisms of several MCT-unrelated weak acid translocating proteins, but utilization of the proton binding and transfer capabilities of the transporter-bound substrate is probably a universal theme for weak acid anion/H⁺ cotransport (Geistlinger et al. 2023). This transporter is over expressed in breast cancer (Arponen et al. 2023). Fasting upregulates MCT1 at the rat blood-brain barrier through PPAR δ activation (Chasseigneaux et al. 2024).  The anticancer effect of androgen deprivation therapy can be enhanced by an MCT1 inhibitor in prostate cancer cells (Kim et al. 2024).  Sulforaphane (SFN)  inhibits non-small cell lung cancer (NSCLC) growth and metastasis by reducing lactate production by regulating the expressions of monocarboxylate transporter 1 (MCT1) and MCT4 that transport lactate across cell membrane (Shi et al. 2024).  The N-terminal signature motif on MCT1 is critical for CD147-mediated trafficking (see TC#s 3.A.3.2.1 and 8.A.23.1.1as well as 2.A.1.13.1) (Seka et al. 2024). A cluster of non-steroidal anti-inflammatory drugs (NSAIDs) are inhibitors of lactate transport via MCT1 (Wegner et al. 2024).  The structures and functions of MCTs, their participation in cancer, and developed inhibitors have been reviewed (Koltai and Fliegel 2024).