Curcumol inhibits the expression of programmed cell death-ligand 1 through crosstalk between hypoxia-inducible factor-1α and STAT3 (T705) signaling pathways in hepatic cancer
Curcumol inhibits the expression of programmed cell death-ligand 1 through crosstalk between hypoxia-inducible factor-1α and STAT3 (T705) signaling pathways in hepatic cancer
复制标题
姜黄酚通过缺氧诱导因子 1 α 和 STAT3 (T705) 信号通路之间的串扰抑制肝癌中程序性细胞死亡配体 1 的表达
DOI：
10.1016/j.jep.2020.112835
复制
发表时间：
2020-07-15
影响因子：
5.4
通讯作者：
Jin, Xuejun
中科院分区：
文献类型：
--
作者：
Zuo, Hong Xiang;Jin, Yong;Jin, Xuejun
民族药理意义：温郁金是一种中草药，通常被用作抗氧化、抗增殖和抗肿瘤药物。姜黄醇是目前作为抗癌药物使用的温郁金挥发油质量控制的代表性指标成分，被收录于2005年版《国家药典》中国版。本研究的目的：从肿瘤免疫治疗的角度探讨姜黄醇的新作用。材料与方法：通过同源模建、分子对接实验、荧光素酶报告实验、四甲基偶氮唑盐比色法、RT-PCR、Western blotting和免疫荧光等方法，在体外研究了姜黄醇抑制细胞程序性死亡配体1(PD-L1)活化的机制。通过EDU标记、克隆形成、流式细胞术、创面愈合、Matrigel Transwell侵袭、导管形成和T细胞杀伤等方法分析细胞增殖、血管生成和T细胞杀伤活性的变化。结果：姜黄醇通过JAK1、JAK2和Src途径抑制磷酸化信号转导和转录激活因子3(p-STAT3)的表达，通过mTOR/p70S6K/eIF4E和MAPK途径抑制缺氧诱导因子-1α(HIF-1α)的蛋白合成。此外，我们揭示了STAT3和HIF-1α信号通路之间的串扰，它们协同调节PD-L1的激活，而姜黄醇在这一调节中发挥了作用。姜黄醇通过抑制PD-L1抑制细胞增殖、S期进展、管状形成、侵袭和转移。此外，姜黄醇还通过抑制PD-L1恢复了细胞毒性T细胞的活性及其对肿瘤细胞的杀伤能力。体内实验证实，姜黄醇通过抑制HIF-1α和p-STAT3(T705)信号通路之间的串扰，抑制肝癌中PD-L1的表达。因此，姜黄醇可能是一种很有前途的先导化合物，用于开发新的靶向抗癌药物。
Ethnopharmacological relevance: Curcuma wenyujin is a Chinese traditional herbal medicine that is commonly used as an anti-oxidant, anti-proliferative, and anti-tumorigenic agent. Curcumol is a representative index component for the quality control of the essential oil of Curcuma wenyujin, which is currently used as an anticancer drug, and is included in the State Pharmacopoeia Commission of the People's Republic of China (2005). However, the mechanisms of action and molecular functions of curcumol are not yet fully elucidated.Aim of the study: This study aimed to identify new effects of curcumol from the perspective of cancer immunotherapy.Materials and methods: The underlying mechanism of the inhibition of programmed cell death-ligand 1 (PD-L1) activation by curcumol was investigated in vitro via homology modeling, molecular docking experiments, luciferase reporter assays, MTT assays, RT-PCR, western blotting, and immunofluorescence assays. Changes in cellular proliferation, angiogenesis, and the tumor-killing activity of T-cells were analyzed via EdU labeling, colony formation, flow cytometry, wound-healing, Matrigel Transwell invasion, tube formation, and T-cell killing. The anti-tumor activity of curcumol was assessed in vivo in a murine xenograft model using Hep3B cells.Results: Curcumol reduced the expression of phosphorylated signal transducer and activator of transcription 3 (p-STAT3) via JAK1, JAK2, and Src pathways and inhibited hypoxia-inducible factor-1 alpha (HIF-1 alpha) protein synthesis via mTOR/p70S6K/eIF4E and MAPK pathways. Furthermore, we revealed crosstalk between STAT3 and HIF-1 alpha pathways, which collaboratively regulated PD-L1 activation, and that curcumol played a role in this regulation. Curcumol inhibited cell proliferation, S-phase progression, tube formation, invasion, and metastasis by inhibiting PD-L1. In addition, curcumol restored the activity of cytotoxic T-cells and their capacity for tumor cell killing by inhibiting PD-L1. In vivo experiments confirmed that curcumol inhibited tumor growth in a xenograft model.Conclusions: These results illustrated that curcumol inhibits the expression of PD-L1 through crosstalk between HIF-1 alpha and p-STAT3 (T705) signaling pathways in hepatic cancer. Thus, curcumol might represent a promising lead compound for the development of new targeted anti-cancer therapeutics.