期刊
PHYTOMEDICINE
卷 81, 期 -, 页码 -出版社
ELSEVIER GMBH
DOI: 10.1016/j.phymed.2020.153425
关键词
Britannin; PD-L1; Myc; HIF-1 alpha; Antitumor
资金
- National Natural Science Foundation of China [81660608, 81760657]
- 111 Project of the base of recruiting talents for disciplinary innovation on natural resources & functional molecules
- 13th five-year program of science and technology of the ministry of education of Jilin province [JJKH20191152KJ]
Britannin inhibits the expression of PD-L1 in tumor cells, which leads to the inhibition of tumor cell proliferation and angiogenesis, as well as enhancement of T cell activity, demonstrating its anticancer effects.
Background: Programmed cell death-ligand 1 (PD-L1) is overexpressed in tumor cells, which causes tumor cells to escape T cell killing, and promotes tumor cell survival, cell proliferation, migration, invasion, and angiogenesis. Britannin is a natural product with anticancer pharmacological effects. Purpose: In this work, we studied the anticancer potential of britannin and explored whether britannin mediated its effect by inhibiting the expression of PD-L1 in tumor cells. Methods: In vitro, the mechanisms underlying the inhibition of PD-L1 expression by britannin were investigated by MTT assay, homology modeling and molecular docking, RT-PCR, western blotting, co-immunoprecipitation, and immunofluorescence. The changes in tumor killing activity, cell proliferation, cell cycle, migration, invasion, and angiogenesis were analyzed by T cell killing assays, EdU labeling, colony formation, flow cytometry, wound healing, matrigel transwell invasion, and tube formation, respectively. In vivo, the antitumor activity of britannin was evaluated in the HCT116 cell xenograft model. Results: Britannin reduced the expression of PD-L1 in tumor cells by inhibiting the synthesis of the PD-L1 protein but did not affect the degradation of the PD-L1 protein. Britannin also inhibited HIF-1 alpha expression through the mTOR/P70S6K/4EBP1 pathway and Myc activation through the Ras/RAF/MEK/ERK pathway. Mechanistically, britannin inhibited the expression of PD-L1 by blocking the interaction between HIF-1 alpha and Myc. In addition, britannin could enhance the activity of cytotoxic T lymphocytes and inhibit tumor cell proliferation and angiogenesis by inhibiting PD-L1. Finally, in vivo observations were confirmed by demonstrating the antitumor activity of britannin in a murine xenograft model. Conclusion: Britannin inhibits the expression of PD-L1 by blocking the interaction between HIF-1 alpha and Myc. Moreover, britannin stabilizes T cell activity and inhibits proliferation and angiogenesis by inhibiting PD-L1 in cancer. The current work highlights the anti-tumor effect of britannin, providing insights into the development of cancer therapeutics via PD-L1 inhibition.
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