Monocarboxylate transporters in cancer

Molecular Metabolism, Год журнала: 2019, Номер 33, С. 48 - 66

Опубликована: Июль 27, 2019

Tumors are highly plastic metabolic entities composed of cancer and host cells that can adopt different phenotypes. For energy production, may use 4 main fuels shuttled in 5 pathways. Glucose glycolysis be coupled to the tricarboxylic acid (TCA) cycle oxidative phosphorylation (OXPHOS) or lactic fermentation proliferating hypoxic cells. Lipids fuel lipolysis, glutamine glutaminolysis, lactate pathway lactate, all which TCA OXPHOS for production. This review focuses on latter pathway. Lactate, is prominently produced by glycolytic tumors, was only recently recognized as a major signaling agent. Its exchanges across membranes gated monocarboxylate transporters MCT1-4. summarizes current knowledge about MCT structure, regulation functions cancer, with specific focus metabolism, lactate-induced angiogenesis MCT-dependent metastasis. It also describes via cell surface receptor GPR81. Lactate MCTs, especially MCT1 MCT4, important contributors tumor aggressiveness. Analyses MCT-deficient (MCT+/- MCT−/-) animals (MCT-mutated) humans indicate they druggable, inhibitors being advanced development phase MCT4 still discovery phase. Imaging fluxes non-invasively using tracer positron emission tomography would further help identify responders treatments.

Язык: Английский

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Mechanisms of Metabolic Reprogramming in Cancer Cells Supporting Enhanced Growth and Proliferation

Cells, Год журнала: 2021, Номер 10(5), С. 1056 - 1056

Опубликована: Апрель 29, 2021

Cancer cells alter metabolic processes to sustain their characteristic uncontrolled growth and proliferation. These alterations include (1) a shift from oxidative phosphorylation aerobic glycolysis support the increased need for ATP, (2) glutaminolysis NADPH regeneration, (3) altered flux through pentose phosphate pathway tricarboxylic acid cycle macromolecule generation, (4) lipid uptake, lipogenesis, cholesterol synthesis, (5) upregulation of one-carbon metabolism production NADH/NADPH, nucleotides, glutathione, (6) amino metabolism, (7) metabolism-based regulation apoptosis, (8) utilization alternative substrates, such as lactate acetate. Altered in cancer is controlled by tumor-host cell interactions, key oncogenes, tumor suppressors, other regulatory molecules, including non-coding RNAs. Changes pathways are dynamic, exhibit plasticity, often dependent on type microenvironment, leading thought Warburg Effect "reverse Effect" plasticity. Understanding complex nature these multiple can development new therapies.

Язык: Английский

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Dual Inhibition of the Lactate Transporters MCT1 and MCT4 Is Synthetic Lethal with Metformin due to NAD+ Depletion in Cancer Cells

Cell Reports, Год журнала: 2018, Номер 25(11), С. 3047 - 3058.e4

Опубликована: Дек. 1, 2018

Highly glycolytic cancer cells prevent intracellular acidification by excreting the end-products lactate and H+ via monocarboxylate transporters 1 (MCT1) 4 (MCT4). We report that syrosingopine, an anti-hypertensive drug, is a dual MCT1 MCT4 inhibitor (with 60-fold higher potency on MCT4) prevents efflux. Syrosingopine elicits synthetic lethality with metformin, of mitochondrial NADH dehydrogenase. NAD+, required for ATP-generating steps glycolysis, regenerated from dehydrogenase or treatment leads to high levels thereby end-product inhibition The loss NAD+ regeneration capacity due combined metformin syrosingopine results in blockade, leading ATP depletion cell death. Accordingly, can be partly restored exogenously provided NAD precursor nicotinamide mononucleotide (NMN), vitamin K2. Thus, pharmacological potential therapy.

Язык: Английский

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A guide to plasma membrane solute carrier proteins

FEBS Journal, Год журнала: 2020, Номер 288(9), С. 2784 - 2835

Опубликована: Авг. 24, 2020

This review aims to serve as an introduction the solute carrier proteins (SLC) superfamily of transporter and their roles in human cells. The SLC currently includes 458 transport 65 families that carry a wide variety substances across cellular membranes. While members this are found throughout organelles, focuses on transporters expressed at plasma membrane. At cell surface, may be viewed gatekeepers milieu, dynamically responding different metabolic states. With altered metabolism being one hallmarks cancer, we also briefly surface play development progression cancer through influence regulating environmental conditions.

Язык: Английский

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Monocarboxylate Transporters (SLC16): Function, Regulation, and Role in Health and Disease

Pharmacological Reviews, Год журнала: 2020, Номер 72(2), С. 466 - 485

Опубликована: Март 6, 2020

The solute carrier family 16 (SLC16) is comprised of 14 members the monocarboxylate transporter (MCT) that play an essential role in transport important cell nutrients and for cellular metabolism pH regulation. MCTs 1-4 have been extensively studied are involved proton-dependent L-lactate, pyruvate, short-chain fatty acids, drugs a wide variety tissues. 1 4 overexpressed number cancers, current investigations focused on inhibition as novel therapeutic strategy cancers. MCT1 has also used strategies aimed at enhancing drug absorption due to its high expression intestine. Other MCT isoforms less well characterized, but ongoing studies indicate MCT6 transports xenobiotics such bumetanide, nateglinide, probenecid, whereas MCT7 characterized ketone bodies. MCT8 MCT10 thyroid hormones, recently, MCT9 carnitine efflux MCT12 creatine transporter. Expressed blood brain barrier, mutations associated with X-linked intellectual disability, known Allan-Herndon-Dudley syndrome. Many hormone, lipid, glucose homeostasis, recent research their potential roles disease, representing promising targets. This review will provide summary literature focusing characterization, function, regulation disposition health disease. SIGNIFICANCE STATEMENT: 14-member transporters (MCTs) plays fundamental maintaining intracellular concentrations broad range endogenous molecules 1, 2, (L-lactate transporters) cancers represent target cancer. Recent highlighted importance glucose, hormone including uptake, transport, MCT11 type 2 diabetes.

Язык: Английский

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Causes, consequences, and therapy of tumors acidosis

Cancer and Metastasis Reviews, Год журнала: 2019, Номер 38(1-2), С. 205 - 222

Опубликована: Март 26, 2019

Язык: Английский

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Short‐Chain Fatty Acid Transporters: Role in Colonic Homeostasis

Comprehensive physiology, Год журнала: 2017, Номер unknown, С. 299 - 314

Опубликована: Дек. 11, 2017

Short-chain fatty acids (SCFA; acetate, propionate, and butyrate) are generated in colon by bacterial fermentation of dietary fiber. Though diffusion protonated form is a significant route, carrier-mediated mechanisms constitute the major route for entry SCFA their anionic into colonic epithelium. Several transport systems operate cellular uptake SCFA. MCT1 (SLC16A1) MCT4 (SLC16A3) H+-coupled mediate electroneutral (H+: stoichiometry; 1:1). expressed both apical membrane basolateral epithelium whereas specifically membrane. SMCT1 (SLC5A8) SMCT2 (SLC5A12) Na+-coupled; SMCT1-mediated electrogenic (Na+: 2:1) SMCT2-mediated exclusively An anion-exchange mechanism also operates which coupled to bicarbonate efflux; molecular identity this exchanger however remains unknown. All these transporters subject regulation, notably substrates themselves; process involves cell-surface receptors with as signaling molecules. There alterations expression ulcerative colitis cancer. The tumor-associated changes occur via transcriptional regulation p53 HIF1α promoter methylation. As obligatory optimal health, responsible transcellular transfer products critical determinants function under physiological conditions disease states. © 2018 American Physiological Society. Compr Physiol 8:299-314, 2018.

Язык: Английский

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Lactate Dehydrogenases as Metabolic Links between Tumor and Stroma in the Tumor Microenvironment

Cancers, Год журнала: 2019, Номер 11(6), С. 750 - 750

Опубликована: Май 29, 2019

Cancer is a metabolic disease in which abnormally proliferating cancer cells rewire pathways the tumor microenvironment (TME). Molecular reprogramming TME helps to fulfill elevated demands for bioenergetics and cellular biosynthesis. One of ways through cell achieve this by regulating expression enzymes. Lactate dehydrogenase (LDH) primary enzyme that converts pyruvate lactate vice versa. LDH also plays significant role nutrient exchange between stroma. Thus, targeting human treating advanced carcinomas may be benefit. LDHA LDHB, two isoenzymes LDH, participate stroma interaction fuel thus could serve as potential anticancer drug targets. This article reviews recent research discussing roles metabolism. As molecular regulation LDHB different remains obscure, we review signaling expression. We highlight on small molecule inhibitors activity emphasize development safer more effective inhibitors. trust will generate interest designing combination therapies based inhibition, with being targeted tumors stromal better treatment outcome.

Язык: Английский

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Hypoxia-Inducible Factors and Cancer

Current Sleep Medicine Reports, Год журнала: 2017, Номер 3(1), С. 1 - 10

Опубликована: Янв. 28, 2017

Язык: Английский

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Double genetic disruption of lactate dehydrogenases A and B is required to ablate the “Warburg effect” restricting tumor growth to oxidative metabolism

Journal of Biological Chemistry, Год журнала: 2018, Номер 293(41), С. 15947 - 15961

Опубликована: Авг. 29, 2018

Язык: Английский

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