期刊
INTERNATIONAL IMMUNOPHARMACOLOGY
卷 93, 期 -, 页码 -出版社
ELSEVIER
DOI: 10.1016/j.intimp.2021.107395
关键词
Z-guggulsterone; PD-L1; Farnesoid X receptor; Non-small cell lung cancer
资金
- National Natural Science Foundation of China, China [81902325]
- Health and Family Planning Commission of Shandong Province, China [2017WS026]
- Key Research and Development Plan of Shandong Province, China [2019GSF107042, 2019GSF107051]
Z-GS has been shown to have anti-tumor effects in NSCLC cells and mouse LLC tumors, while also increasing PD-L1 expression levels through inhibition of FXR and activation of Akt and Erk1/2 signaling pathways. These findings suggest potential for synergistic combined therapies in NSCLC.
Programmed death-ligand 1 (PD-L1) is an immune checkpoint molecule, that is overexpressed in non-small cell lung cancer (NSCLC) and has been associated with the response to anti-PD-1/PD-L1 immunotherapy. Z-guggulsterone (Z-GS), an active compound extracted from the gumresin of the Commiphora mukul tree, has been shown to have anti-tumor effects in NSCLC in our previous study. However, whether Z-GS could affect PD-L1 expression levels in tumor cells remains unknown. In this study, we verified the inhibitory effects of Z-GS on NSCLC cell viability and cell cycle progression in vitro, and mouse Lewis lung carcinoma (LLC) tumor growth in vivo. Notably, Z-GS treatment increased PD-L1 surface and mRNA expression levels, and gene transcription in NSCLC cells, in a dose-and time-dependent manner. Mechanistic experiments showed that the upregulation of PD-L1 was mediated, partly by farnesoid X receptor inhibition, and partly by the activation of the Akt and Erk1/2 signaling pathways in Z-GS-treated NSCLC cells. In vivo, Z-GS treatment dose-dependently increased PD-L1 expression levels in mouse LLC tumor models. Overall, our findings demonstrated a promoting role for Z-GS in PD-L1 expression in NSCLC and provided mechanistic insights, that may be used for further investigation into synergistic combined therapies.
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