Downregulation of DNA-PKcs suppresses P-gp expression via inhibition of the Akt/NF-κB pathway in CD133-positive osteosarcoma MG-63 cells

作者：Li, Ka; Li, Xin; Tian, Jiguang; Wang, Hongliang; Pan, Jingbo; Li, Jianmin^*

来源：Oncology Reports, 2016, 36(4): 1973-1980.

DOI：10.3892/or.2016.4991

• osteosarcoma
• DNA-dependent protein kinase catalytic subunit
• P-glycoprotein
• cancer stem cells
• Akt/NF-kappa B pathway
• drug resistance

The development of chemoresistance is closely linked to the plateau of the survival rate in osteosarcoma (OS) patients. CD133-positive (CD133(+)) OS cells are known as cancer stem cells (CSCs) in OS and exhibit the characteristic of chemoresistance. In this study, CD133(+) and CD133-negative (CD133(-)) MG-63 cells were isolated by magnetic activated cell sorting (MACS). We verified that CD133(+) MG-63 cells were more resistant to cisplatin (CDDP) than CD133(-) MG-63 cells. DNA-dependent protein kinase catalytic subunit (DNA-PKcs) and P-glycoprotein (P-gp) were expressed at higher levels in the CD133(+) MG-63 cells compared with those levels in the CD133(-) MG-63 cells, whereas downregulation of DNA-PKcs by small interfering RNA (siRNA) decreased chemoresistance to CDDP and P-gp expression at the mRNA and protein levels in these cells. This indicated that DNA-PKcs was correlated with P-gp expression in the CD133(+) MG-63 cells. The Akt/NF-kappa B pathway was hyperactivated in the CD133(+) MG-63 cells, whereas inhibition of the Akt/NF-kappa B pathway downregulated P-gp expression. In addition, downregulation of DNA-PKcs suppressed the activity of the Akt/NF-kappa B pathway. These results revealed that downregulation of DNA-PKcs could decrease P-gp expression via suppression of the Akt/NF-kappa B pathway in CD133(+) MG-63 cells. Therefore, inhibition of DNA-PKcs decreases P-gp expression and sensitizes OS CSCs to chemotherapeutic agents in vitro, which needs to be further validated in vivo.

• 出版日期2016-10
• 单位山东大学