苍术素通过 PI3K/AKT/mTOR 和 p38MAPK 信号通路抑制胆管癌细胞的迁移并诱导自噬。

Atractylodin inhibited the migration and induced autophagy in cholangiocarcinoma cells via PI3K/AKT/mTOR and p38MAPK signalling pathways.

机构信息

Chulabhorn International College of Medicine, Thammasat University, Rangsit Center, Klong Luang, Pathum Thani, Thailand.

Center of Excellence in Pharmacology and Molecular Biology of Malaria and Cholangiocarcinoma, Chulabhorn International College of Medicine, Thammasat University, Rangsit Center, Klong Luang, Pathum Thani, Thailand.

出版信息

J Pharm Pharmacol. 2021 Aug 12;73(9):1191-1200. doi: 10.1093/jpp/rgab036.

DOI:10.1093/jpp/rgab036

PMID:33885818

Abstract

OBJECTIVES

The effects of atractylodin (ATD), the bioactive compound from Atractylodes lancea, on migration and autophagy status of cholangiocarcinoma cell line were investigated.

METHODS

Cytotoxic activity and effects on cell migration and invasion were evaluated by MTT and trans-well assay, respectively. Autophagy and underlying molecular mechanisms were investigated using flow cytometry and western blot analysis.

KEY FINDINGS

ATD regulated the activity of PI3K/AKT/mTOR and p38MAPK signalling pathways which contributed to autophagy induction. HuCCT-1 cell growth was inhibited by ATD in a time- and dose-dependent manner. ATD inhibited the migration and invasion of HuCCT1 cells in a concentration-dependent manner. It also induced autophagy in HuCCT1 cells in a time- and dose-dependent manner. The SB202190 (autophagy inducer) and 3-MA (autophagy inhibitor) significantly increased and decreased the rate of ATD-induced autophagy, respectively. The 24 h exposure of ATD inhibited the phosphorylation of phosphatidylinositol-3-kinase (PI3K), protein kinase B (AKT), mammalian target of rapamycin (mTOR), mitogen-activated protein kinase (p38MAPK) and increased Beclin-1 expression and LC3 conversion. It also reduced p-AKT/AKT, p-mTOR/mTOR and p-p38MAPK/p38MAPK.

CONCLUSIONS

ATD inhibits the proliferation and induces CCA cell autophagy via regulating PI3K/AKT/mTOR and p38MAPK signalling pathways.

摘要

目的

研究苍术素（ATD），白术中的生物活性化合物，对胆管癌细胞系迁移和自噬状态的影响。

方法

通过 MTT 和 Transwell 测定分别评估细胞毒性和对细胞迁移和侵袭的影响。通过流式细胞术和 Western blot 分析研究自噬和潜在的分子机制。

主要发现

ATD 调节了 PI3K/AKT/mTOR 和 p38MAPK 信号通路的活性，这有助于自噬的诱导。ATD 以时间和剂量依赖的方式抑制 HuCCT-1 细胞的生长。ATD 以浓度依赖的方式抑制 HuCCT1 细胞的迁移和侵袭。它还以时间和剂量依赖的方式诱导 HuCCT1 细胞中的自噬。SB202190（自噬诱导剂）和 3-MA（自噬抑制剂）分别显著增加和减少 ATD 诱导的自噬率。24 小时暴露于 ATD 抑制了磷酸肌醇-3-激酶（PI3K）、蛋白激酶 B（AKT）、雷帕霉素靶蛋白（mTOR）、丝裂原激活蛋白激酶（p38MAPK）的磷酸化，并增加了 Beclin-1 表达和 LC3 转化。它还降低了 p-AKT/AKT、p-mTOR/mTOR 和 p-p38MAPK/p38MAPK。