Role of Human Monocarboxylate Transporter 1 (hMCT1) and 4 (hMCT4) in Tumor Cells and the Tumor Microenvironment

Figures & data

Figure 1 Prediction model of hMCT1 (a) and hMCT4 (b).

Notes: Adapted from Sasaki S, Kobayashi M, Futagi Y, et al. Crucial residue involved in L-lactate recognition by human monocarboxylate transporter 4 (hMCT4). PLoS One. 2013;8(7):e67690. Creative Commons.²⁸

Figure 2 Glucose metabolic process. Glucose enters cells via glucose transporters (GULT). Many enzymes are involved in the process of anaerobic glycolysis. The production of pyruvate from glucose is catalyzed by three key enzymes: hexokinase (HK), 6-phosphofructokinase 1 (PKF1) and pyruvate kinase (PKM). Pyruvate is catalyzed by lactate dehydrogenase A (LDHA) to lactate. The tricarboxylic acid cycle (TCA) process is catalyzed by several key enzymes: citrate synthase (CS), isocitrate dehydrogenase (IDH) and ketoglutarate dehydrogenase complex (KGDHC). Blue areas (eg, red skeletal muscle, heart and neurons) and green areas (eg, white skeletal muscle fibers and astrocytes) indicate lactate transport in normal cells.

Figure 3 Schematic of lactate shuttling from cell to cell through the MCTs. Hypoxic cancer cells and cancer-associated fibroblasts (CAFs) use glucose to produce lactate through glycolysis, and lactate is transported out of the cell by MCT4. Aerobic cancer cells transport lactate through MCT1. Vascular endothelial cells transport lactic acid into cells through MCT1 and promote angiogenesis through NF-KB/IL8 pathway (㊉: activate).

Figure 4 MCTs partial adjustment mode diagram.

Notes: ㊉: Activate, ㊀: suppress.

Abbreviations: TCF/LEF, T-cell factor/lymphoenhancer factor; CBP, CREB-binding protein; MACC1, metastasis-associated in colon cancer-1.

Table 1 Summary of MCTs Regulation

MCTs	Regulating Modes	Ref
MCT1/4	Nrf2	[143]
	CAIV/IX	[146,147]
	Promoter methylation	[132,133]
MCT1	P53	[94]
	Myc	[95,102–104]
	Butyrate	[108–110]
	Wnt /β-catenin	[140,141]
	GPR81/109A	[110,114]
	MACC1	[124]
	PMA	[125,126]
	Luminal leptin	[129]
	AP1	[144]
	Urf1/2	[142]
	NF-κB	[109,144]
	CAII	[145]
	MiR-124	[134]
	miR-495	[135]
	miR-342-3p	[136]
MCT4	HIF-1	[88]
	AMPK	[150,151]
	PKC	[151,152]
	FBI-1	[149]
	IL-1β	[153]
	miR-1	[137]
	miR-145	[138]
	miR-148	[138]
	miR-425-5p	[139]

Table 2 Summary of Inhibitors

MCTs	Inhibitors	Ki or EC50*	Ref
MCT1	AZD3965	1.6nM	[156–161]
	AR-C155858	2.3nM	[57,163,164]
	7-Aminocarboxycoumarin Derivatives	11nM	[164,167]
	Indole cyanoacrylate	–	[42]
	Pteridine Dione and Trione	–	[183]
	BAY-8002	7.9nM; 10nM	[168]
MCT4	VB124	8.6nM	[169,170]
	Bindarit	30.2uM	[171,172]
	ACF	4.6mM	[184]
MCTs	CHC	0.99uM	[47,173–176]
	ACCA	1mM	[11,177]
	N,N-dialkyl cyanocinnamic acids	–	[165,178]
	Isobutyrate derivatives	–	[171,179]
	BIC	40uM	[180]
	Bendazak	36uM	[180]

Notes: *Ki: The concentration of the corresponding free inhibitor when 50% of the substrate is bound by the inhibitor. EC50: The concentration of the inhibitor corresponding to 50% of the maximum biological effect can be achieved after a specific exposure time.

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