Multifunctional roles of lactate transporters in wound healing and metastasis
Increased glycolytic metabolism is a common feature of motile cells, particularly during wound healing and metastasis. In order to maintain increased rates of glycolysis, the cell expresses high levels of glycolytic transporters for glucose uptake and lactate efflux. Monocarboxylate transporter 4 (MCT4) is a proton coupled lactate transporter that is preferentially expressed in glycolytic cells and tissues. The focus of these studies was to understand the function of MCT4 in cell motility. Using various biochemical, cell-based, and molecular biological techniques, we uncovered a role for MCT4 in cell movement during wound healing and metastasis. We found that MCT4 expression was increased in the leading edge of motile cells where it associates with CD147 and β1-integrin, proteins involved in matrix-metalloproteinase induction and cell-matrix adhesion, respectively. Upon silencing of MCT4, cell motility was slowed in metastatic breast cancer cells and following scratch-wounding of a human RPE cell line. Interestingly, we found that expression of MCT4 and the glucose transporter, GLUT1, was regulated by the coagulation factor receptor, tissue factor (TF). TF expression is reported to be increased in cancer cells where it was suggested to play a role in cell proliferation and metastasis. The results of this work showed that silencing TF resulted in decreased expression of MCT4 and GLUT1, as well as decreased cell proliferation and motility. TF activation can initiate signaling through the PI3K signaling pathway, which contributes to TF modulation of cell movement. We found that treatment of cancer cells with the PI3K inhibitor, LY294002, decreased levels of MCT4 and GLUT1, as well as TF. In addition, chronic fluvastatin treatment, which blocks TF activation and signaling, lowered cellular levels of MCT4 and GLUT1 and slowed cell proliferation and motility. The results of these studies suggest that MCT4 is a multifunctional protein that modulates cell movement both in wound healing and metastasis. These findings provide a novel link between MCT4 expression and TF signaling, and indicate that each of these proteins is a potential target of statin drugs.