The overexpression of BI-1 induces an acidic extracellular pH due to alterations of mitochondrial function, leading to cancer metastasis through anaerobic glucose metabolism. In this study, ion transporters such as sodium hydrogen exchangers (NHE) and monoamine carboxylate transporters (MCTs) were studied in BI-1-overexpressing HT1080 cells (BI-1 cells). The extracellular pH became acidic as culture time of BI-1 cells increased, while intracellular pH stayed relatively stable at pH 7.2. The expression of MCTs increased in BI-1 cells as culture time passed. 5-(N-ethyl-N-isopropyl) amiloride or dimethylamiloride, NHE inhibitor, abrogated the elevated MCT expression, indicating that MCT followed NHE activation. An MCT inhibitor, lonidamine, regulated the acidification of extracellular pH, also inhibiting both increased cancer cell migration and infiltration and MMP2/9 activity. The inhibition of either NHE or MCT affected the intracellular pH, leading to a severely acidic intracellular pH and cell death. In BI-1 cells, the activation of ion transporters such as NHE or MCT may offer a survival strategy against metabolism-associated acidic stresses. These findings suggest that BI-1 can lead cancer invasion and metastasis by inducing extracellular environment acidic.

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