Lysyl oxidase-like-1 enhances lung metastasis when lactate accumulation and monocarboxylate transporter expression are involved

The role that lysyl oxidase-like-1 (LOXL-1) may play in cancer metastasis due to its specific collagen accumulation characteristics has not been investigated extensively. This study was performed to examine the role of LOXL-1 in cancer metastasis. In vitro and in vivo cancer metastasis experiments were performed with B16F10 cells. Using the immunoblotting technique, the expression of LOXL-1, monocarboxylate transporter (MCT)1/2 and matrix metalloproteinase (MMP)2/9 was examined in a cell culture model and in primary and metastatic site samples from non-small cell lung carcinoma patients. Immunohistochemistry was also performed. According to immunohistochemical analysis of the non-small cell lung carcinoma patient samples, LOXL-1, MCT1/2 and MMP2/9 were expressed more highly in metastatic sites compared to primary sites. In in vivo studies, LOXL-1-overexpressing B16F10 cells yielded higher numbers of cancer nodules following their injection into mouse tail veins. Transfection of LOXL-1 siRNA into the cells prior to injection blocked lung metastasis. In vitro, the overexpression of LOXL-1 increased cell mobility and invasiveness, with increased extracellular accumulation of lactate at a low pH. The lactate transporter, MCT1/2, was highly expressed in LOXL-1-overexpressing cells. LOXL-1 knockdown through siRNA inhibited cell motility and invasiveness, showing relatively lower lactate accumulation and expression of MCT1/2 than under control conditions. This study elucidates extracellular pH-associated matrix degradation as a potential mechanism for LOXL-1-induced cancer metastasis.