PD-1/PD-L1 enhanced cisplatin resistance in gastric cancer through PI3K/AKT mediated P-gp expression.

Abstract

BACKGROUND\nProgrammed cell death receptor 1 (PD-1) is an immunosuppressive molecule expressed on T cells, and its ligand (PD-L1) which expressed on tumor cells play pivotal roles in regulating host immune responses. However, little is known whether PD-1/PD-L1 axis could directly activates intracellular oncogenic signaling pathways in tumor cells, leading to tumor resistance.\n\n\nMETHODS\nIn the present study, the expression of PD-1 and PD-L1 in the tissues of gastric cancer was detected by western blot and immunofluorescence. The effect of PD-L1-Fc and cisplatin on resistant gastric cancer cells was examined by MTT assay and Flow Cytometry. In addition. The effect of PD-L1-Fc on the expression of P-gp in gastric cancer cells and resistant gastric cancer cells was detected by quantitative real-time reverse-transcription PCR (qRT-PCR) and western blot. The molecular mechanisms of the regulation of cisplatin and PD-L1-Fc treatment were evaluated by western blot.\n\n\nRESULTS\nWe found that the level of PD-1 was significantly increased in human gastric cancer tissues and drug-resistant gastric cancer cells and P-gp was the same result. The PD-L1 could reduce the level of cell damage caused by cisplatin. In addition, we found PD-L1 can also up-regulate the expression of P-gp. Mechanistically, PD-L1 activated the PI3K/AKT signaling pathway in which PI3K/AKT pathway inhibition attenuated the upregulation of P-gp.\n\n\nCONCLUSION\nPD-1/PD-L1 enhanced cisplatin resistance in gastric cancer through PI3K/AKT mediated P-gp expression.