AR-C155858 is a potent inhibitor of monocarboxylate transporters MCT1 and MCT2 that binds to an intracellular site involving transmembrane helices 7–10

Ovens, Matthew J.; Davies, Andrew; Wilson, Marieangela C.; Murray, Clare; Halestrap, Andrew P.

doi:10.1042/bj20091515

Cited by 217 publications

(215 citation statements)

References 52 publications

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“…Cultured astrocytes are net lactate producers. To clarify whether the accumulation of lactate was due to increased production or impaired release, astrocytes were exposed to NH + 4 in the presence of the monocarboxylate transporter (MCT) blocker AR-C155858 (26), which in these cells abrogates lactate transport (24). As shown in Fig.…”

Section: Resultsmentioning

confidence: 99%

NH4+ triggers the release of astrocytic lactate via mitochondrial pyruvate shunting

Lerchundi

Fernández‐Moncada

Contreras-Baeza

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Neural activity is accompanied by a transient mismatch between local glucose and oxygen metabolism, a phenomenon of physiological and pathophysiological importance termed aerobic glycolysis. Previous studies have proposed glutamate and K + as the neuronal signals that trigger aerobic glycolysis in astrocytes. Here we used a panel of genetically encoded FRET sensors in vitro and in vivo to investigate the participation of NH + 4 , a by-product of catabolism that is also released by active neurons. Astrocytes in mixed cortical cultures responded to physiological levels of NH + 4 with an acute rise in cytosolic lactate followed by lactate release into the extracellular space, as detected by a lactate-sniffer. An acute increase in astrocytic lactate was also observed in acute hippocampal slices exposed to NH + 4 and in the somatosensory cortex of anesthetized mice in response to i.v. NH + 4 . Unexpectedly, NH + 4 had no effect on astrocytic glucose consumption. Parallel measurements showed simultaneous cytosolic pyruvate accumulation and NADH depletion, suggesting the involvement of mitochondria. An inhibitor-stop technique confirmed a strong inhibition of mitochondrial pyruvate uptake that can be explained by mitochondrial matrix acidification. These results show that physiological NH + 4 diverts the flux of pyruvate from mitochondria to lactate production and release. Considering that NH + 4 is produced stoichiometrically with glutamate during excitatory neurotransmission, we propose that NH + 4 behaves as an intercellular signal and that pyruvate shunting contributes to aerobic lactate production by astrocytes.B rain tissue is almost exclusively energized by the oxidation of glucose. However, during neuronal activation, there is a larger increase in local glucose consumption relative to oxygen consumption (1). As this mismatch occurs in the presence of normal or augmented oxygen levels, it has been termed aerobic glycolysis, paralleling the signal detected by functional magnetic resonance imaging (2). Aerobic glycolysis and its associated lactate surge are causally linked to diverse functions of the brain in health and disease (3-10). Two signals are known to trigger aerobic glycolysis in brain tissue: glutamate and K + , which are released by active neurons and stimulate glycolysis in astrocytes (11,12).Neurons produce as much NH + 4 as they produce glutamate, both molecules being stoichiometrically linked in the glutamateglutamine cycle (13). Brain tissue NH + 4 increases within seconds of neural activation (14-16) and is quickly released to the interstitium (17, 18) to be captured by astrocytes through K + channels and transporters (19). It is well established that chronic exposure to pathological levels of NH + 4 such as those observed during liver failure has a major impact on brain metabolism, but it is not known whether this molecule may affect energy metabolism at physiological levels, particularly within the time scale of synaptic transmission. A previous study showed a reversible rise in brain tissue la...

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Section: Resultsmentioning

confidence: 99%

NH4+ triggers the release of astrocytic lactate via mitochondrial pyruvate shunting

Lerchundi

Fernández‐Moncada

Contreras-Baeza

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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“…Although there is currently no known inhibitor for MCT7, we were able to test the role of MCT1 in ␤-HB transport across the RPE using an MCT1/2 inhibitor (AR-C155858, Ref. 21). Fully differentiated and polarized hfRPE cells on Transwell filters (R T Ͼ 500 ⍀⅐cm 2 ) were used in these transport experiments.…”

Section: Resultsmentioning

confidence: 99%

The Retinal Pigment Epithelium Utilizes Fatty Acids for Ketogenesis

Adijanto

Moffat

et al. 2014

Journal of Biological Chemistry

148

138

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Background: RPE cells derive fatty acids from phagocytized photoreceptor outer segments. Results: RPE cells metabolize palmitate to produce ␤-hydroxybutyrate (␤-HB), a ketone body the retina can use as a metabolic substrate. Conclusion: RPE cells produce ␤-HB as a potential substrate for photoreceptor cells in the outer retina. Significance: This is a novel form of RPE-retina interaction that may be important for retinal cell health and function.

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“…However, so far, only isoform specific MCT1 inhibitors (e.g., AR-C155858; ref. 28) have been evaluated in phase I/II trials. Interestingly, treatment of patients with statins, which are known to inhibit MCT4 (29), reduced the risk of RCC (30).…”

Section: Discussionmentioning

confidence: 99%

DNA Methylation of the SLC16A3 Promoter Regulates Expression of the Human Lactate Transporter MCT4 in Renal Cancer with Consequences for Clinical Outcome

Fisel

Kruck

Winter

et al. 2013

Clinical Cancer Research

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Purpose: The monocarboxylate transporter 4 (MCT4) is a metabolic target in tumor biology because it mediates lactate transport across membranes resulting in antiapoptotic effects. Cell experiments support the importance of MCT4 in clear cell renal cell carcinoma (ccRCC). In this study, we assessed the prognostic potential of MCT4 expression in ccRCC and its epigenetic regulation by DNA methylation as novel predictive marker for patient outcome using independent ccRCC cohorts.Experimental Design: MCT4 protein expression was quantified in 207 ccRCC and corresponding nontumor tissues. Data of an independent ccRCC cohort from The Cancer Genome Atlas (TCGA) were analyzed on MCT4 mRNA (n ¼ 482) and DNA methylation (n ¼ 283) level. The findings on MCT4 expression and DNA methylation in the SLC16A3 promoter were validated in a third cohort (n ¼ 64). Promoter activity assays were conducted in four RCC cell lines.Results: MCT4 protein expression was upregulated (P < 0.0001) in ccRCC and showed significant association with cancer-related death. Upregulation of MCT4 mRNA expression (P < 0.00001) was confirmed in the TCGA cohort. Single CpG sites correlated inversely with mRNA expression and were associated with overall survival in Kaplan-Meier analyses [HR ¼ 0.39; 95% confidence interval (CI), 0. Conclusion:We identified SLC16A3 promoter DNA methylation as a novel epigenetic mechanism for MCT4 regulation in ccRCC with first evidence of a biological rationale for prognosis and clinical outcome.

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AR-C155858 is a potent inhibitor of monocarboxylate transporters MCT1 and MCT2 that binds to an intracellular site involving transmembrane helices 7–10

Cited by 217 publications

References 52 publications

NH4+ triggers the release of astrocytic lactate via mitochondrial pyruvate shunting

NH4+ triggers the release of astrocytic lactate via mitochondrial pyruvate shunting

The Retinal Pigment Epithelium Utilizes Fatty Acids for Ketogenesis

DNA Methylation of the SLC16A3 Promoter Regulates Expression of the Human Lactate Transporter MCT4 in Renal Cancer with Consequences for Clinical Outcome

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