Panaxadiol inhibits programmed cell death-ligand 1 expression and tumour proliferation via hypoxia-inducible factor (HIF)-1α and STAT3 in human colon cancer cells
Panaxadiol inhibits programmed cell death-ligand 1 expression and tumour proliferation via hypoxia-inducible factor (HIF)-1α and STAT3 in human colon cancer cells
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人参二醇通过缺氧诱导因子 (HIF)-1 α 和 STAT3 抑制人结肠癌细胞中程序性细胞死亡配体 1 的表达和肿瘤增殖
DOI：
10.1016/j.phrs.2020.104727
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发表时间：
2020-05-01
影响因子：
9.3
通讯作者：
Jin, Xuejun
中科院分区：
文献类型：
--
作者：
Wang, Zhe;Li, Ming Yue;Jin, Xuejun
人参二醇（Panaxadiol）是人参根中发现的一种三萜皂苷元单体化合物，具有神经保护和抗肿瘤等多种生物活性。然而，人参二醇发挥抗癌作用的机制尚不清楚。本研究旨在研究人参二醇对人结肠癌细胞中程序性细胞死亡配体1（PD-L1）表达和肿瘤增殖的潜在活性，并确定其潜在机制。结果显示，人参二醇显示出如通过细胞毒性测定评估的很小的细胞毒性，并且以剂量依赖性方式在蛋白质和mRNA水平上显著抑制PD-L1表达。此外，人参二醇通过磷酸肌醇3-激酶（PI 3 K）和丝裂原活化蛋白激酶（MAPK）途径抑制缺氧诱导的缺氧诱导因子（HIF）-1 α的合成，而不影响HIF-1 α的降解。同时，人参二醇通过JAK 1、JAK 2和Src通路抑制STAT 3活化。此外，在T细胞与肿瘤细胞共培养系统中，人参二醇预处理增强了细胞毒性T淋巴细胞（CTL）的活性，并恢复了其杀伤肿瘤细胞的能力。免疫沉淀显示人参二醇通过阻断HIF-1 α和STAT 3之间的相互作用抑制PD-L1表达。通过集落形成和EdU标记试验进一步证实了人参二醇对肿瘤增殖的抑制作用。体内异种移植实验也证实了人参二醇的抗增殖作用。综上所述，目前的研究强调了人参二醇的抗肿瘤作用，为通过PD-L1抑制开发癌症治疗提供了见解。
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-Ll expression at the protein and mRNA level in a dose-dependent manner. Furthermore, panaxadiol supressed the hypoxia-induced synthesis of hypoxia-inducible factor (HIF)-1 alpha via the phosphoinositide 3-kinase (PI3K) and mitogen-activated protein kinase (MAPK) pathways without affecting HIF-1 alpha 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-1 alpha 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 antitumour effect of panaxadiol, providing insights into development of cancer therapeutic through PD-L1 inhibition.