Abstract
Metastatic cancer cells increase glucose consumption and metabolism via glycolysis, producing large quantities of lactate. Recent work has shown that lactate efflux is mediated by monocarboxylate transporters (MCT), which are composed of a catalytic unit (MCT) and an accessory subunit (CD147), comprising the functional lactate transporter. CD147, an extracellular matrix metalloproteinase (MMP) inducer, is highly expressed in metastatic cancer cells. Because aerobic glycolysis is a hallmark of metastatic cancer, we examined whether increases in CD147 expression were linked to MCT expression in MDA-MB-231, a highly metastatic breast cancer cell line. MCT4 mRNA and protein expression were increased in MDA-MB-231 cells compared with cells derived from normal mammary tissue. MCT4 colocalized with CD147 in the plasma membrane and in membrane blebs shed from the cell surface. Small interfering RNA-mediated silencing of MCT4 impaired the maturation and trafficking of CD147 to the cell surface, resulting in accumulation of CD147 in the endoplasmic reticulum. Silencing MCT4 also resulted in fewer membrane blebs and decreased migration of MDA-MB-231 cells in vitro. Knockdown of CD147 resulted in loss of MCT4 in the plasma membrane and accumulation of the transporter in endolysosomes. These studies establish for the first time that increased expression of CD147 in metastatic cancer cells is coupled to the up-regulation of MCT4. The synergistic activities of the MCT/CD147 complex could facilitate migration of tumor cells by CD147-mediated MMP induction and lactate-stimulated angiogenesis and hyaluronan production. These data provide a molecular link between two hallmarks of metastatic cancer: the glycolytic switch and increased expression of CD147.
Highlights
A hallmark of invasive cancer is the up-regulation of glycolytic genes and an increased dependence on glycolysis for the production of ATP [1, 2]
Because many cancer cells exhibit an increase in glucose consumption and metabolism via glycolysis, we compared monocarboxylate transporters (MCT), CD147, and GLUT1 expression in the highly invasive breast cancer cell line MDA-MB-231 with a breast cell line derived from a normal mammary gland (HTB-125)
Using reverse transcription-PCR (RT-PCR) analysis, we found that MCT4 and CD147 mRNAs were expressed at higher levels in MDA-MB-231 cells than in HTB-125 cells
Summary
A hallmark of invasive cancer is the up-regulation of glycolytic genes and an increased dependence on glycolysis for the production of ATP [1, 2]. The switch from oxidative to glycolytic metabolism of glucose is accompanied by increased expression of the glucose transporter GLUT1 and glucose uptake. This feature of cancer cells, first described by Warburg more than 50 years ago, has been confirmed in animal models and humans through the use of 18-fluoro-deoxyglucose positron emission tomography [3, 4]. MCT1 is the most widely expressed member of this family and has recently been shown to be elevated in a variety of cancers, including neuroblastoma [7] and colorectal carcinomas [8]. Expression of MCT4 protein in metastatic cancer cells has not been examined; MCT4 recently appeared on a list of genes that are up-regulated by the transcription factor hypoxia-inducible factor (HIF)-1, which can regulate the metabolic switch in metastatic cancer cells [2, 13]
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