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PD-1/PD-L1 enhanced cisplatin resistance in gastric cancer through PI3K/AKT mediated P-gp expression
Lijun Wu1, Shiyi Cai1, Yiyun Deng1
1School of Pharmacy, Anhui Medical University, Hefei, China.
Background:
Programmed 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.
Methods:
In 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.
Results:
We 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.
Conclusion:
PD-1/PD-L1 enhanced cisplatin resistance in gastric cancer through PI3K/AKT mediated P-gp expression.
Insights
Programmed cell death receptor 1 (PD-1) and its ligand (PD-L1) increase cisplatin resistance in gastric cancer. This occurs via the PI3K/AKT pathway, which upregulates P-glycoprotein (P-gp) expression in tumor cells.
Area of Science:
- Immunology
- Oncology
- Molecular Biology
Background:
- Programmed cell death receptor 1 (PD-1) is an immunosuppressive molecule on T cells.
- Its ligand, PD-L1, on tumor cells regulates immune responses.
- The direct impact of the PD-1/PD-L1 axis on tumor cell signaling and resistance is unclear.
Purpose of the Study:
- To investigate the role of the PD-1/PD-L1 axis in gastric cancer drug resistance.
- To explore the molecular mechanisms underlying PD-L1-mediated resistance to cisplatin.
- To determine if PD-1/PD-L1 directly activates oncogenic pathways in gastric cancer cells.
Main Methods:
- Western blot and immunofluorescence to detect PD-1 and PD-L1 expression in gastric cancer tissues.
- MTT assay and Flow Cytometry to assess the effects of PD-L1-Fc and cisplatin on resistant cells.
- Quantitative real-time reverse-transcription PCR (qRT-PCR) and western blot to analyze P-glycoprotein (P-gp) expression and signaling pathways.
Main Results:
- PD-1 and P-gp levels were significantly increased in human gastric cancer tissues and drug-resistant cells.
- PD-L1 reduced cisplatin-induced cell damage and upregulated P-gp expression.
- PD-L1 activated the PI3K/AKT signaling pathway, and its inhibition attenuated P-gp upregulation.
Conclusions:
- The PD-1/PD-L1 axis enhances cisplatin resistance in gastric cancer.
- This resistance is mediated by PI3K/AKT pathway activation, leading to increased P-gp expression.
