3-去氧姜黄素通过 JNK/p38MAPKs 信号通路诱导人食管癌细胞中 ROS 介导的细胞凋亡和细胞周期停滞。
The 3-deoxysappanchalcone induces ROS-mediated apoptosis and cell cycle arrest via JNK/p38 MAPKs signaling pathway in human esophageal cancer cells.
机构信息
Department of Pharmacy, College of Pharmacy, Mokpo National University, Jeonnam 58554, Republic of Korea.
College of Korean Medicine, Dongshin University, Naju, Jeonnam 58245, Republic of Korea.
出版信息
Phytomedicine. 2021 Jun;86:153564. doi: 10.1016/j.phymed.2021.153564. Epub 2021 Apr 4.
BACKGROUND
The 3-deoxysappanchalcone (3-DSC), a chemical separated from Caesalpinia sappan L, has been substantiated to display anti-inflammatory, anti-influenza, and anti-allergy activities according to previous studies. However, the underlying mechanisms of action on esophageal cancer remain unknown.
PURPOSE
The present research aims to survey the action mechanisms of 3-DSC in esophageal squamous cell carcinoma (ESCC) cells in vitro.
METHODS
Evaluation of cytotoxicity was determined by MTT tetrazolium salt assay and soft agar assay. Cell cycle distribution, apoptosis induction, reactive oxygen species (ROS) generation, mitochondrial membrane potential (MMP), and multi-caspases activity were appreciated by Muse™ Cell Analyzer. The expressions of cell cycle- and apoptosis-related proteins were presented using Western blotting.
RESULTS
3-DSC blocked cell growth and colony formation ability in a concentration-dependent manner and invoked apoptosis, G2/M cell cycle arrest, ROS production, MMP depolarization, and multi-caspase activity. Furthermore, Western blotting results demonstrated that 3-DSC upregulated the expression of phospho (p)-c-jun NH2-terminal kinases (JNK), p-p38, cell cycle regulators, pro-apoptotic proteins, and endoplasmic reticulum (ER) stress-related proteins whereas downregulated the levels of anti-apoptotic proteins and cell cycle promoters. The effects of 3-DSC on ROS induction were counteracted by pretreatment with N-acetyl-L-cysteine (NAC). Also, our results indicated that p38 (SB203580) and JNK (SP600125) inhibitor slightly inhibited 3-DSC-induced apoptosis. These results showed that 3-DSC-related G2/M phase cell cycle arrest and apoptosis by JNK/p38 MAPK signaling pathway in ESCC cells were mediated by ROS.
CONCLUSION
ROS generation by 3-DSC in cancer cells could be an attractive strategy for apoptosis of cancer cells by inducing cell cycle arrest, ER stress, MMP loss, multi-caspase activity, and JNK/p38 MAPK pathway. Our findings suggest that 3-DSC is a promising novel therapeutic candidate for both prevention and treatment of esophageal cancer.
背景
3-去氧苏木酮（3-DSC）是从苏木中分离出的一种化学物质，先前的研究已经证实其具有抗炎、抗流感和抗过敏活性。然而，其在食管癌中的作用机制尚不清楚。
目的
本研究旨在体外研究 3-DSC 对食管鳞状细胞癌细胞（ESCC）的作用机制。
方法
采用 MTT 四唑盐法和软琼脂克隆形成实验测定细胞毒性。通过 Muse 细胞分析仪评价细胞周期分布、凋亡诱导、活性氧（ROS）生成、线粒体膜电位（MMP）和多半胱氨酸酶活性。采用 Western blot 检测细胞周期和凋亡相关蛋白的表达。
结果
3-DSC 呈浓度依赖性地抑制细胞生长和集落形成能力，并诱导细胞凋亡、G2/M 期细胞周期阻滞、ROS 生成、MMP 去极化和多半胱氨酸酶活性。此外，Western blot 结果表明，3-DSC 上调磷酸化（p）-c-jun NH2 末端激酶（JNK）、p-p38、细胞周期调节剂、促凋亡蛋白和内质网（ER）应激相关蛋白的表达，而下调抗凋亡蛋白和细胞周期促进剂的水平。用 N-乙酰-L-半胱氨酸（NAC）预处理可逆转 3-DSC 诱导的 ROS 生成。此外，我们的结果表明，p38（SB203580）和 JNK（SP600125）抑制剂轻度抑制了 3-DSC 诱导的细胞凋亡。这些结果表明，3-DSC 通过 JNK/p38 MAPK 信号通路诱导 ESCC 细胞 G2/M 期细胞周期阻滞和凋亡，ROS 在此过程中发挥重要作用。
结论
3-DSC 在癌细胞中产生 ROS 可能是通过诱导细胞周期阻滞、内质网应激、MMP 丧失、多半胱氨酸酶活性和 JNK/p38 MAPK 通路诱导癌细胞凋亡的一种有吸引力的策略。我们的研究结果表明，3-DSC 是一种有前途的新型治疗候选物，可用于预防和治疗食管癌。
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