2. Academic Validation
  3. Z-guggulsterone induces PD-L1 upregulation partly mediated by FXR, Akt and Erk1/2 signaling pathways in non-small cell lung cancer

Z-guggulsterone induces PD-L1 upregulation partly mediated by FXR, Akt and Erk1/2 signaling pathways in non-small cell lung cancer

  • Int Immunopharmacol. 2021 Apr;93:107395. doi: 10.1016/j.intimp.2021.107395.
Han Tian 1,  Yanni Gui 1,  Yuanhui Wei 1,  Bin Shang 2,  Jian Sun 3,  Shan Ma 4,  Wenjie You 5,  Shujuan Jiang 6
Affiliations

Affiliations

  • 1 Department of Respiratory and Critical Care Medicine, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250021, China.
  • 2 Department of Thoracic Surgery, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250021, China; Department of Thoracic Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong 250021, China.
  • 3 Department of Respiratory and Critical Care Medicine, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250021, China; Department of Respiratory and Critical Care Medicine, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong 250021, China; Shandong Key Laboratory of Infectious Respiratory Disease, Jinan, Shandong 250021, China.
  • 4 Innovative Institute of Chinese Medicine and Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan, Shandong 250014, China.
  • 5 Department of Respiratory and Critical Care Medicine, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250021, China; Department of Respiratory and Critical Care Medicine, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong 250021, China; Shandong Key Laboratory of Infectious Respiratory Disease, Jinan, Shandong 250021, China. Electronic address: youwenjie655@163.com.
  • 6 Department of Respiratory and Critical Care Medicine, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250021, China; Department of Respiratory and Critical Care Medicine, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong 250021, China; Shandong Key Laboratory of Infectious Respiratory Disease, Jinan, Shandong 250021, China. Electronic address: docjiangshujuan@163.com.
PMID: 33529916 DOI: 10.1016/j.intimp.2021.107395
Abstract

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.

Keywords

Farnesoid X receptor; Non-small cell lung cancer; PD-L1; Z-guggulsterone.

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