PKC epsilon inhibits isolation and sternness of side population cells via the suppression of ABCB1 transporter and PI3K/Akt, MAPK/ERK signaling in renal cell carcinoma cell line 769P

摘要

Protein kinase C epsilon (PICCE), a member of the novel PKC family, is known to be a transforming oncogene and tumor biomarker for many human solid cancers including renal cell carcinoma (RCC). We isolated side population (SP) cells from the RCC 769P cell line, and proved that those cells possess cancer stem cell (CSC) characteristics. In this study, to identify the function of PKC epsilon in cancer stemness of 769P SP cells, we reduced the expression of PKC epsilon in those cells, following the results demonstrated that PKC epsilon depletion had a negative correlation with the existence of SP cells in 769P cell line. Down-regulation of PKC epsilon also suppresses the CSC potential of sorted 769P SP cells in several ways: proliferation potential, resistance to chemotherapeutics and in vivo tumor formation ability. Our study also reveals that PKC epsilon is associated with ABCB1 and this association probably contributed to the SP cells isolation from 769P cell line. Furthermore, the expression of ABCB1 is directly regulated by PKC epsilon. Additionally, after the depletion of PKC epsilon, the phosphorylation of pAkt, pStat3 and pERK was apparently suppressed in 769P SP cells, whereas PKC epsilon overexpression could promote the phosphorylation of AKT, STAT3 and ERK in 769P Non SP cells. Overall, PKC epsilon down-regulation suppresses sorting and the cancer stem-like phenotype of RCC 769P SP cells through the regulation of ABCB1 transporter and the PI3K/Akt, Stat3 and MAPK/ERK pathways that are dependent on the phosphorylation effects. Thus, PKC epsilon may work as an important mediator in cancer stem cell pathogenesis of renal cell cancer. (C) 2016 Elsevier Ireland Ltd. All rights reserved.