ERK MAPK 信号调节剂 ACA-28 通过诱导黑色素瘤和胰腺癌细胞中的 ROS 发挥抗癌作用

2区 生物学 Q1 Biochemistry, Genetics and Molecular Biology
Teruaki Takasaki, Yasuyuki Hamabe, Kenta Touchi, Golam Iftakhar Khandakar, Takeshi Ueda, Hitoshi Okada, Kazuko Sakai, Kazuto Nishio, Genzoh Tanabe, Reiko Sugiura
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引用次数: 0

摘要

在各种人类癌症中,细胞外信号调节激酶(ERK)MAPK 通路失调,被认为是一种有吸引力的癌症治疗靶点。因此,该通路的几种抑制剂正在开发中,其中一些已经应用于临床。我们之前发现了一种抗癌化合物 ACA-28,它具有一种独特的特性,能优先诱导黑色素瘤细胞发生 ERK 依赖性凋亡。为了全面了解 ACA-28 对生物细胞的影响,我们使用 DNA 微阵列对暴露于 ACA-28 的人黑色素瘤 SK-MEL-28 细胞进行了全基因表达分析。转录组分析发现,ACA-28 处理后上调最多的基因通路是核因子红细胞 2 相关因子 2(Nrf2),这是一种对抗氧化应激的主转录因子。同样,ACA-28 还具有提高活性氧(ROS)和 Nrf2 蛋白水平的特性,而 Nrf2 蛋白通常会被蛋白酶体降解所抑制,并在氧化应激时被激活。此外,ROS 清除剂 N- 乙酰半胱氨酸会显著削弱 ACA-28 的抗癌活性。因此,ACA-28 可激活 Nrf2 信号,并部分通过其刺激 ROS 的特性发挥抗癌活性。有趣的是,与SK-MEL-28相比,人A549癌细胞的Nrf2蛋白组成水平较高,对ACA-28表现出抗性。瞬时过表达 Nrf2 也会增加细胞对 ACA-28 的抵抗力,而敲除 Nrf2 则会产生相反的效果。因此,上调 Nrf2 信号可保护癌细胞免受 ACA-28 介导的细胞死亡。值得注意的是,Nrf2抑制剂ML385大大增强了ACA-28在胰腺癌细胞T3M4和PANC-1中诱导细胞死亡的特性。我们的数据表明,Nrf2在决定癌细胞对ACA-28的易感性方面起着关键作用,并为结合Nrf2抑制剂和ACA-28的癌症治疗提供了一种新策略。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
ACA-28, an ERK MAPK Signaling Modulator, Exerts Anticancer Activity through ROS Induction in Melanoma and Pancreatic Cancer Cells
The extracellular signal-regulated kinase (ERK) MAPK pathway is dysregulated in various human cancers and is considered an attractive therapeutic target for cancer. Therefore, several inhibitors of this pathway are being developed, and some are already used in the clinic. We have previously identified an anticancer compound, ACA-28, with a unique property to preferentially induce ERK-dependent apoptosis in melanoma cells. To comprehensively understand the biological cellular impact induced by ACA-28, we performed a global gene expression analysis of human melanoma SK-MEL-28 cells exposed to ACA-28 using a DNA microarray. The transcriptome analysis identified nuclear factor erythroid 2-related factor 2 (Nrf2), a master transcription factor that combats oxidative stress, as the most upregulated genetic pathway after ACA-28 treatment. Consistently, ACA-28 showed properties to increase the levels of reactive oxygen species (ROS) as well as Nrf2 protein, which is normally repressed by proteasomal degradation and activated in response to oxidative stresses. Furthermore, the ROS scavenger N-acetyl cysteine significantly attenuated the anticancer activity of ACA-28. Thus, ACA-28 activates Nrf2 signaling and exerts anticancer activity partly via its ROS-stimulating property. Interestingly, human A549 cancer cells with constitutively high levels of Nrf2 protein showed resistance to ACA-28, as compared with SK-MEL-28. Transient overexpression of Nrf2 also increased the resistance of cells to ACA-28, while knockdown of Nrf2 exerted the opposite effect. Thus, upregulation of Nrf2 signaling protects cancer cells from ACA-28-mediated cell death. Notably, the Nrf2 inhibitor ML385 substantially enhanced the cell death-inducing property of ACA-28 in pancreatic cancer cells, T3M4 and PANC-1. Our data suggest that Nrf2 plays a key role in determining cancer cell susceptibility to ACA-28 and provides a novel strategy for cancer therapy to combine the Nrf2 inhibitor and ACA-28.
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来源期刊
CiteScore
13.20
自引率
0.00%
发文量
1274
审稿时长
3-8 weeks
期刊介绍: Oxidative Medicine and Cellular Longevity is a unique peer-reviewed, Open Access journal that publishes original research and review articles dealing with the cellular and molecular mechanisms of oxidative stress in the nervous system and related organ systems in relation to aging, immune function, vascular biology, metabolism, cellular survival and cellular longevity. Oxidative stress impacts almost all acute and chronic progressive disorders and on a cellular basis is intimately linked to aging, cardiovascular disease, cancer, immune function, metabolism and neurodegeneration. The journal fills a significant void in today’s scientific literature and serves as an international forum for the scientific community worldwide to translate pioneering “bench to bedside” research into clinical strategies.
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