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Review
. 2016 Apr 26;7(17):23141-55.
doi: 10.18632/oncotarget.8153.

The altered glucose metabolism in tumor and a tumor acidic microenvironment associated with extracellular matrix metalloproteinase inducer and monocarboxylate transporters

Xiaofeng Li  1   2   3 , Xiaozhou Yu  1   2   3 , Dong Dai  1   2   3 , Xiuyu Song  1   2   3 , Wengui Xu  1   2   3
Affiliations
Review

The altered glucose metabolism in tumor and a tumor acidic microenvironment associated with extracellular matrix metalloproteinase inducer and monocarboxylate transporters

Xiaofeng Li et al. Oncotarget. .

Abstract

Extracellular matrix metalloproteinase inducer, also knowns as cluster of differentiation 147 (CD147) or basigin, is a widely distributed cell surface glycoprotein that is involved in numerous physiological and pathological functions, especially in tumor invasion and metastasis. Monocarboxylate transporters (MCTs) catalyze the proton-linked transport of monocarboxylates such as L-lactate across the plasma membrane to preserve the intracellular pH and maintain cell homeostasis. As a chaperone to some MCT isoforms, CD147 overexpression significantly contributes to the metabolic transformation of tumor. This overexpression is characterized by accelerated aerobic glycolysis and lactate efflux, and it eventually provides the tumor cells with a metabolic advantage and an invasive phenotype in the acidic tumor microenvironment. This review highlights the roles of CD147 and MCTs in tumor cell metabolism and the associated molecular mechanisms. The regulation of CD147 and MCTs may prove to be with a therapeutic potential for tumors through the metabolic modification of the tumor microenvironment.

Keywords: extracellular matrix metalloproteinase inducer; glycolysis; monocarboxylate transporters; p53; tumor acidic microenvironment.

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Conflict of interest statement

The authors declare no conflicts of interest.

Figures

Figure 1
Figure 1. Schematic representation of the non-metabolic molecular mechanism of tumor progression associated with CD147 overexpression
First, CD147 colocalizes and interacts with integrin in the invasion and metastasis of tumor cells via integrin α3β1-mediated FAK-paxillin and FAK-PI3K-Ca2+ signal pathways and integrin α6β1-mediated PI3K-Ca2+ signaling pathways, respectively. Second, the annexin II−CD147 interaction is involved in rearranging the cytoskeleton via inhibiting Rho signaling pathways and amoeboid movement by CD147 through inhibiting annexin II phosphorylation in the EMS, thus promoting membrane localization of WAVE2, Rac1 activation, formation of lamellipodia and mesenchymal movement via the integrin-FAK-PI3K/PIP3 signaling pathway. Third, CD147 stimulates tumor angiogenesis by elevating VEGF and MMPs via PI3K-Akt signaling pathway. In addition, CD147 is involved in EMT via a signaling cascade: TGF-β−PI3K/Akt−GSK3β−Snail−Slug−CD147. Finally, CD147 expression protects tumor cells from anoikis and starvation-induced autophagy at least in part by reducing Bim and downregulating autophagy-relating gene ATG6/Beclin1, respectively. Akt: also known as protein kinase B (PKB); Bim: Bcl-2 interacting mediator of cell death; EMT: epithelial mesenchymal transition; EMS: endomembrane system; FAK: focal adhesion kinase; GSK-3β: glycogen synthase kinase-3β; MMP: matrix metalloproteinase; PDK1: phosphoinositide dependent protein kinase-1; PI3K: phosphatidylinositol 3-kinase; PIP3: phosphatidylinositol 3,4,5-trisphosphate; Rac1: Ras-related C3 botulinum toxin substrate 1; RhoA: Ras homolog gene family, member A; Rock: Rho-kinase; Snail: zinc-finger transcriptional factor Snail; Slug: zinc-finger transcriptional factor Slug; TGF-β1: transforming growth factor-β1; VEGF: vascular endothelial growth factor; WAVE2: WASP-family verprolin homologous protein 2.
Figure 2
Figure 2. Schematic depicting the regulation of altered glucose metabolism by CD147 in a tumor
Hypoxia in the tumor microenvironment induces the upregulation of CD147 expression by a combined effect of transcription factor HIF-1 on HRE of CD147 and SP1 on the activation of CD147 promotor. The overexpression of CD147 promotes aerobic glycolysis mediated by the activation of the PI3K/Akt/MDM2 pathway, subsequently promotion of p53 degradation and inhibiting the downregulation of GLUT1/4 gene expression and suppression of PFK by p53 in the glycolytic metabolism and repressing mitochondrial oxidative respiration via downregulation of PGC1a, TFAM, and p53R2 in a p53-dependent manner at the same time. The glycolytic phenotype of tumor leads to increased production of lactic acid, which has to be exported across the plasma membrane in order to prevent cell death, due to cellular acidosis. Lactate is pumped out from cells mainly through two H+/lactate co-transporters, MCT1 and MCT4, to maintain homeostasis in the intracellular pH of tumors (MCT1 is bidirectional). CD147 serves as a chaperone to assist in the surface expression, folding, stability, appropriate location and functionality of MCT1 and MCT4. ATP: adenosine triphosphate; Akt: also known as protein kinase B (PKB); GLUT1/4: glucose transporter 1/4; HIF: hypoxia-inducible factor; HRE: hypoxia response element; MCT1/4: monocarboxylate transporter 1/4; MDM2: mouse double minute 2 homolog; PFK: phosphofructokinase; PGC-1: peroxisome proliferators-activated receptor-γ coactivator-1; PI3K: phosphatidylinositol 3-kinase; P53: protein 53; P53R2: p53-inducible ribonu cleotidereductase small submit 2; SP1: specificity protein 1 transcription factor; TFAM: mitochondrial transcription factor A.
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