杨梅素通过 ROS 依赖性激活 IRE1α/JNK 诱导结直肠癌细胞发生 Noxa 介导的细胞凋亡。

Gambogenic acid induces Noxa-mediated apoptosis in colorectal cancer through ROS-dependent activation of IRE1α/JNK.

机构信息

Laboratory of Inflammation and Molecular Pharmacology, School of Basic Medical Sciences & Biomedical Research Institute, Hubei University of Medicine, Hubei Key Laboratory of Embryonic Stem Cell Research, Hubei Key Laboratory of Wudang Local Chinese Medicine Research, Hubei University of Medicine, Shiyan 442000, China.

出版信息

Phytomedicine. 2020 Nov;78:153306. doi: 10.1016/j.phymed.2020.153306. Epub 2020 Aug 18.

DOI:10.1016/j.phymed.2020.153306

PMID:32854039

Abstract

BACKGROUND

Gambogenic acid (GNA), an active component of Garcinia hanburyi Hook.f. (Clusiaceae) (common name gamboge), exerts anti-inflammatory and antitumor properties. However, the underlying mechanism of GNA in colorectal cancer (CRC) is still not well understood.

PURPOSE

This study aimed to investigate the antitumor effects and mechanisms of GNA on CRC in vitro and in vivo.

METHODS

Cell viability, colony formation and cell apoptosis assays were performed to determine the antitumor effects of GNA. qRT-PCR and Western blotting were performed to evaluate the expression of genes or proteins affected by GNA in vitro and in vivo. HCT116 colon cancer xenografts and the APC mice model were used to confirm the antitumor effects of GNA on CRC in vivo.

RESULTS

GNA induced Noxa-mediated apoptosis by inducing reactive oxygen species (ROS) generation and c-Jun N-terminal kinase (JNK) activation. Moreover, GNA triggered endoplasmic reticulum (ER) stress, which subsequently activated inositol-requiring enzyme-1α (IRE1α) leading to JNK phosphorylation. ROS scavenger attenuated GNA-induced IRE1α activation and JNK phosphorylation. Knockdown of IRE1α also prevented GNA-induced JNK phosphorylation. In vivo, GNA suppressed tumor growth and progression in HCT116 colon cancer xenografts and the APC mices model.

CONCLUSION

These findings revealed that GNA induced Noxa-mediated apoptosis by activating the ROS/IRE1α/JNK signaling pathway in CRC both in vitro and in vivo. GNA is therefore a promising antitumor agent for CRC treatment.

摘要

背景

山竹胍酸（GNA）是藤黄科藤黄属植物（俗称吉纳）的一种活性成分，具有抗炎和抗肿瘤特性。然而，GNA 对结直肠癌（CRC）的作用机制尚不清楚。

目的

本研究旨在探讨 GNA 在体外和体内对 CRC 的抗肿瘤作用及其机制。

方法

采用细胞活力、集落形成和细胞凋亡实验来确定 GNA 的抗肿瘤作用。qRT-PCR 和 Western blot 用于评估 GNA 对体外和体内基因或蛋白表达的影响。使用 HCT116 结肠癌细胞异种移植和 APC 小鼠模型来体内验证 GNA 对 CRC 的抗肿瘤作用。

结果

GNA 通过诱导活性氧（ROS）生成和 c-Jun N-末端激酶（JNK）激活诱导 Noxa 介导的细胞凋亡。此外，GNA 引发内质网（ER）应激，进而激活肌醇需求酶 1α（IRE1α）导致 JNK 磷酸化。ROS 清除剂减弱了 GNA 诱导的 IRE1α 激活和 JNK 磷酸化。IRE1α 的敲低也阻止了 GNA 诱导的 JNK 磷酸化。体内实验表明，GNA 抑制了 HCT116 结肠癌细胞异种移植和 APC 小鼠模型中的肿瘤生长和进展。