Regulation of expression of ABCB1 and LRP genes by mitogen-activated protein kinase/extracellular signal-regulated kinase pathway and its role in generation of side population cells in canine lymphoma cell lines.

The concept of the cancer stem cell (CSC) has been recognized as key for elucidation of the mechanisms that confer the multidrug resistance (MDR) phenotype to tumor cells, and the side population (SP) fraction has been shown to be enriched by cells with the CSC phenotype. The purpose of the present study was to identify the mechanism that induces a difference of phenotype between the SP and the remaining major population (MP) using two canine lymphoma cell lines. Expression levels of ABCB1 and LRP genes, which encode efflux pumps, were significantly higher in the SP than in the MP. Microarray analysis revealed up-regulation of the expression of transforming growth factor-β (TGF-β) type II receptor in SP compared with MP, and the mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) pathway was more up-regulated in the SP than in the MP. Stimulation of the MAPK/ERK pathway significantly increased the mRNA expression of both ABCB1 and LRP genes. These results indicate increased expression of the efflux pumps through the MAPK/ERK pathway in SP cells.