Regulation of Monocarboxylic Acid Transporter 1 Trafficking by the Canonical Wnt/β-Catenin Pathway in Rat Brain Endothelial Cells Requires Cross-talk with Notch Signaling

Abstract

The transport of monocarboxylate fuels such as lactate, pyruvate, and ketone bodies across brain endothelial cells is mediated by monocarboxylic acid transporter 1 (MCT1). Although the canonical Wnt/␤-catenin pathway is required for rodent blood-brain barrier development and for the expression of associated nutrient transporters, the role of this pathway in the regulation of brain endothelial MCT1 is unknown. Here we report expression of nine members of the frizzled receptor family by the RBE4 rat brain endothelial cell line. Monocarboxylic acid transporter 1 (MCT1)-dependent lactate transport is critical for various biological processes, including muscle and colonocyte metabolism, kidney glomerulus function, immune suppression, tumor progression, long-term memory formation, and oligodendroglial metabolism (1-7). In the brain, MCT1 is highly expressed in the endothelial cells of the neurovascular unit and the so called blood-brain barrier (BBB). 3 MCT1 is responsible for the blood-brain transport of monocarboxylic substrates such as lactate, pyruvate, ketone bodies, and some monocarboxylic drugs (8 -10). Furthermore, by facilitating brain-to-blood efflux of lactic acid, MCT1 represents an important pathway to reduce lactic acidosis associated with hypoxia and stroke, in which decreased lactic acidosis predicts a better prognosis (11, 12). MCT1-dependent delivery of ketone bodies from the peripheral circulation into the brain is especially critical for supporting neonatal brain development, maintaining energy metabolism of hibernating animals, and treating childhood epilepsy and glucose transporter 1 deficiency syndrome with the ketogenic diet (13-17). MCT1 also transports drugs into the CNS, including valproic acid to treat epilepsy and bipolar disorders (18) and 3-bromopyruvate to inhibit glycolytic tumors, implicating the transporter as an important therapeutic target (19). Therefore, understanding the regulation of brain endothelial MCT1 is of particular significance for brain health and disease.However, research on the regulation of MCT1 by signaling pathways in brain endothelial cells is limited and merits further investigation. One signaling pathway that is crucial for initiating rodent BBB development is the canonical Wnt/␤-catenin pathway (20,21), which also plays a critical role in many other biological processes, e.g. dorsal-ventral axis formation during embryonic development, cell proliferation, tissue self-renewal, and cancer progression (22)(23)(24)(25). Activity of the Wnt/␤-catenin pathway depends on nuclear ␤-catenin, which is normally kept low in resting cells. An intracellular multiprotein complex consisting of adenomatous polyposis coli (APC), axin, glycogen synthase kinase 3 ␤ (GSK-3 ␤), and casein kinase 1 ␣ (CK1 ␣) phosphorylates cytosolic ␤-catenin. This phosphorylation leads to recognition and ubiquitination of ␤-catenin by the E3 ubiquitin ligase ␤-TrCP and subsequent proteasomal degradation (26, 27). Wnt ligands signal by binding to the extracellular portion of frizzled family receptors...

Metabolic advantages and vulnerabilities in brain metastases

“…Studies have shown that cell cycle control genes and Wnt signaling are upregulated in BMs (19). In endothelial cells from rat brains, the Wnt/β-catenin pathway interacts with the Notch pathway to increase the amount of monocarboxylic acid transporter 1 (MCT1) protein (20). MCT1 promotes pyruvate export and cell proliferation and is upregulated in glycolytic cancer cells, therefore MCT1 inhibitors block proliferation and may be useful cancer therapeutics (21).…”

Posttranslational Regulation of Organic Anion Transporters by Ubiquitination: Known and Novel

“…Our investigation of OATs in cultured cells and in rat kidney slices demonstrated that the PKC‐induced acceleration of OAT internalization is due to an elevation in OAT ubiquitination . Ubiquitination‐mediated functional regulation has been observed with other members of solute carrier family of drug transporters . Mass spectroscopy analysis revealed that the ubiquitination of OAT occurs through the conjugation of a lysine 48‐linked polyubiquitin chain to the transporter .…”

Radial Extracorporeal Shock Wave Therapy Enhances the Proliferation and Differentiation of Neural Stem Cells by Notch, PI3K/AKT, and Wnt/β-catenin Signaling

“…This effect was likely caused, at least in part, by an upregulated PI3K/AKT pathway, Wnt/β-catenin signaling, and Notch1 signaling. Although not discussed in this research, crosstalk between these three pathways is also a pivotal factor for the fate of NSCs 52 . Our data provide novel insight into the molecular mechanisms of rEWST on NSCs and important preclinical references supporting the basis for further development of neurological function recovery promoted by NSCs recruitment.…”