Parthenolide Inhibits Synthesis and Promotes Degradation of Programmed Cell Death Ligand 1 and Enhances T Cell Tumor-Killing Activity,Journal of Agricultural and Food Chemistry

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Parthenolide Inhibits Synthesis and Promotes Degradation of Programmed Cell Death Ligand 1 and Enhances T Cell Tumor-Killing Activity
Journal of Agricultural and Food Chemistry ( IF 5.7 ) Pub Date : 2024-09-12 , DOI: 10.1021/acs.jafc.4c04916
Xin Zhe Liu ₁ , Yi Tai ₁ , Yu Bao Hou ₁ , Shen Cao ₁ , Jing Han ₁ , Ming Yue Li ₁ , Hong Xiang Zuo ₁ , Yue Xing ₁ , Xuejun Jin ₁ , Juan Ma ₁

Affiliation

Parthenolide is a germacrane sesquiterpene lactone separated from the traditional medicinal plant feverfew. Previous studies have shown that parthenolide possesses many pharmacological activities, involving anti-inflammatory and anticancer activities. However, the antitumor mechanism of parthenolide has not been fully elucidated. Thus, we investigate the potential antitumor mechanisms of parthenolactone. We predicted through network pharmacology that parthenolide may target HIF-1α to interfere with the occurrence and development of cancer. We found that parthenolide inhibited PD-L1 protein synthesis through mTOR/p70S6K/4EBP1/eIF4E and RAS/RAF/MEK/MAPK signaling pathways and promoted PD-L1 protein degradation through the lysosomal pathway, thereby inhibiting PD-L1 expression. Immunoprecipitation and Western blotting results demonstrated that parthenolide inhibited PD-L1 expression by suppressing HIF-1α and RAS cooperatively. We further proved that parthenolide inhibited cell proliferation, migration, invasion, and tube formation via down-regulating PD-L1. Moreover, parthenolide increased the effect of T cells to kill tumor cells. In vivo xenograft assays further demonstrated that parthenolide suppressed the growth of tumor xenografts. Collectively, we report for the first time that parthenolide enhanced T cell tumor-killing activity and suppressed cell proliferation, migration, invasion, and tube formation by PD-L1. The current study provides new insight for the development of parthenolide as a novel anticancer drug targeting PD-L1.

中文翻译：

小白菊内酯抑制程序性细胞死亡配体 1 的合成并促进其降解，增强 T 细胞肿瘤杀伤活性

小白菊内酯是从传统药用植物小白菊中分离出来的一种香叶倍半萜内酯。先前的研究表明小白菊内酯具有多种药理活性，包括抗炎和抗癌活性。然而，小白菊内酯的抗肿瘤机制尚未完全阐明。因此，我们研究了小茴香内酯的潜在抗肿瘤机制。我们通过网络药理学预测小白菊内酯可能靶向HIF-1α来干扰癌症的发生和发展。我们发现小白菊内酯通过mTOR/p70S6 K /4EBP1/eIF4E和RAS/RAF/MEK/MAPK信号通路抑制PD-L1蛋白合成，并通过溶酶体途径促进PD-L1蛋白降解，从而抑制PD-L1表达。免疫沉淀和Western blotting结果表明，小白菊内酯通过协同抑制HIF-1α和RAS来抑制PD-L1表达。我们进一步证明小白菊内酯通过下调PD-L1抑制细胞增殖、迁移、侵袭和管形成。此外，小白菊内酯还增强了T细胞杀死肿瘤细胞的作用。体内异种移植物测定进一步证明小白菊内酯抑制肿瘤异种移植物的生长。总的来说，我们首次报道小白菊内酯通过 PD-L1 增强 T 细胞肿瘤杀伤活性并抑制细胞增殖、迁移、侵袭和管形成。目前的研究为小白菊内酯作为靶向PD-L1的新型抗癌药物的开发提供了新的见解。

更新日期：2024-09-12

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