Bone marrow-derived mesenchymal stem cells increase drug resistance in CD133-expressing gastric cancer cells by regulating the PI3K/AKT pathway

Abstract

Bone marrow-derived mesenchymal stem cells (BM-MSCs) are recruited to primary tumours to compose the tumour microenvironment. In various cancers, CD133-positive cells have been shown to possess cancer stem cell properties that confer chemoresistance. This study aimed to investigate the role of BM-MSCs in the anti-tumour drug resistance of CD133-expressing gastric cancer cells and explore the underlying mechanisms that governing this role. We found that CD133⁺ gastric cancer cells displayed more resistance to chemotherapeutics than CD133^- cells. In addition, BM-MSCs increased the anti-apoptotic abilities and chemoresistance of CD133⁺ cells via upregulation of Bcl-2 and downregulation of BAX. Mechanistically, BM-MSCs triggered activation of the PI3K/Akt signalling cascade in CD133⁺ cells. Blocking the PI3K/Akt pathway inhibited the promotion of chemoresistance. Furthermore, BM-MSCs enhanced the drug resistance of CD133-overexpressing cells in vitro and in vivo, but not that of CD133-knockdown cells, which demonstrated the contribution of CD133 to this process. In conclusion, we demonstrated that BM-MSCs increased the anti-apoptotic abilities and drug resistance of CD133-expressing cells via activation of the PI3K/Akt pathway following Bcl-2 upregulation and BAX downregulation, in which CD133 played a significant role. Targeting this route may help improve the efficacy of chemotherapy in gastric cancer.

Keywords: Apoptosis; CD133; Cancer stem cells; Drug resistance; Gastric cancer; Mesenchymal stem cells.