Panaxadiol inhibits programmed cell death-ligand 1 expression and tumour proliferation via hypoxia-inducible factor (HIF)-1α and STAT3 in human colon cancer cells.

Abstract

Panaxadiol is a triterpenoid sapogenin monomeric compound found in the roots of Panax ginseng and has a variety of biological activities such as neuroprotective and anti-tumour functions. However, the mechanisms how panaxadiol exerts the anticancer effects remain unknown. The current study aimed to investigate the potential activity of panaxadiol on programmed cell death-ligand 1 (PD-L1) expression and tumour proliferation in human colon cancer cells and to identify the underlying mechanism. Results showed that panaxadiol showed little cytotoxicity as assessed by a cytotoxicity assay and significantly inhibited PD-L1 expression at the protein and mRNA level in a dose-dependent manner. Furthermore, panaxadiol supressed the hypoxia-induced synthesis of hypoxia-inducible factor (HIF)-1α via the phosphoinositide 3-kinase (PI3K) and mitogen-activated protein kinase (MAPK) pathways without affecting HIF-1α degradation. Simultaneously, panaxadiol inhibited STAT3 activation through the JAK1, JAK2, and Src pathways. Moreover, pre-treatment with panaxadiol enhanced the activity of cytotoxic T lymphocytes (CTL) and regained their capacity of tumour cell killing in a T cell and tumour cell co-culture system. Immunoprecipitation showed that panaxadiol inhibited PD-L1 expression by blocking the interaction between HIF-1α and STAT3. The inhibitory effect of panaxadiol on tumour proliferation was further demonstrated by colony formation and EdU labelling assays. The anti-proliferative effect of panaxadiol was also proved by a xenograft assay in vivo. Taken together, the current work highlights the anti-tumour effect of panaxadiol, providing insights into development of cancer therapeutic through PD-L1 inhibition.

• Authors: Zhe Wang, Ming Yue Li, Zhi Hong Zhang, Hong Xiang Zuo, Jing Ying Wang, Yue Xing, MyongHak Ri, Hong Lan Jin, Cheng Hua Jin, Guang Hua Xu, Lian Xun Piao, Chang Gao Jiang, Juan Ma, Xuejun Jin
• Journal: Pharmacological research (Pharmacol Res) Vol. 155 Pg. 104727 (05 2020) ISSN: 1096-1186 [Electronic] Netherlands
• PMID: 32113874 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2020 Elsevier Ltd. All rights reserved.

Chemical References

• Antineoplastic Agents
• B7-H1 Antigen
• CD274 protein, human
• Ginsenosides
• HIF1A protein, human
• Hypoxia-Inducible Factor 1, alpha Subunit
• STAT3 Transcription Factor
• STAT3 protein, human
• panaxadiol

Topics

• Animals
• Antineoplastic Agents (pharmacology, therapeutic use)
• B7-H1 Antigen (genetics, metabolism)
• Cell Line
• Cell Proliferation (drug effects)
• Colonic Neoplasms (drug therapy, immunology, metabolism)
• Ginsenosides (pharmacology, therapeutic use)
• Humans
• Hypoxia-Inducible Factor 1, alpha Subunit (genetics, metabolism)
• Mice, Inbred BALB C
• Mice, Nude
• STAT3 Transcription Factor (genetics, metabolism)
• T-Lymphocytes (drug effects, immunology)