Dyari Herryawan Ryadi Eziwar, Rawling Tristan, Chen Yongjuan, Sudarmana William, Bourget Kirsi, Dwyer Julie M, Allison Sarah E, Murray Michael
Discipline of Pharmacology, School of Medical Sciences, Sydney Medical School, University of Sydney, Sydney, New South Wales, Australia.
School of Bioscience and Biotechnology, Faculty of Science and Technology, Universiti Kebangsaan Malaysia, Bangi, Malaysia; and.
FASEB J. 2017 Dec;31(12):5246-5257. doi: 10.1096/fj.201700033R. Epub 2017 Aug 10.
A saturated analog of the cytochrome P450-mediated ω-3-17,18-epoxide of ω-3-eicosapentaenoic acid (C20E) activated apoptosis in human triple-negative MDA-MB-231 breast cancer cells. This study evaluated the apoptotic mechanism of C20E. Increased cytosolic cytochrome c expression and altered expression of pro- and antiapoptotic B-cell lymphoma-2 proteins indicated activation of the mitochondrial pathway. Caspase-3 activation by C20E was prevented by pharmacological inhibition and silencing of the JNK and p38 MAP kinases (MAPK), upstream MAPK kinases MKK4 and MKK7, and the upstream MAPK kinase kinase apoptosis signal-regulating kinase 1 (ASK1). Silencing of the death receptor TNF receptor 1 (TNFR1), but not Fas, DR4, or DR5, and the adapters TRADD and TNF receptor-associated factor 2, but not Fas-associated death domain, prevented C20E-mediated apoptosis. B-cell lymphoma-2 homology 3-interacting domain death agonist (Bid) cleavage by JNK/p38 MAPK linked the extrinsic and mitochondrial pathways of apoptosis. In further studies, an antibody against the extracellular domain of TNFR1 prevented apoptosis by TNF-α but not C20E. These findings suggest that C20E acts intracellularly at TNFR1 to activate ASK1-MKK4/7-JNK/p38 MAPK signaling and to promote Bid-dependent mitochondrial disruption and apoptosis. In studies, tumors isolated from C20E-treated nu/nu mice carrying MDA-MB-231 xenografts showed increased TUNEL staining and decreased Ki67 staining, reflecting increased apoptosis and decreased proliferation, respectively. ω-3-Epoxy fatty acids like C20E could be incorporated into treatments for triple-negative breast cancers.-Dyari, H. R. E., Rawling, T., Chen, Y., Sudarmana, W., Bourget, K., Dwyer, J. M., Allison, S. E., Murray, M. A novel synthetic analogue of ω-3 17,18-epoxyeicosatetraenoic acid activates TNF receptor-1/ASK1/JNK signaling to promote apoptosis in human breast cancer cells.
细胞色素P450介导的ω-3-二十碳五烯酸（C20E）的ω-3-17,18-环氧化物的饱和类似物可激活人三阴性MDA-MB-231乳腺癌细胞的凋亡。本研究评估了C20E的凋亡机制。胞质细胞色素c表达增加以及促凋亡和抗凋亡B细胞淋巴瘤-2蛋白表达改变表明线粒体途径被激活。通过药理学抑制以及沉默JNK和p38丝裂原活化蛋白激酶（MAPK）、上游MAPK激酶MKK4和MKK7以及上游MAPK激酶激酶凋亡信号调节激酶1（ASK1），可阻止C20E对Caspase-3的激活。沉默死亡受体TNF受体1（TNFR1）而非Fas、DR4或DR5，以及衔接蛋白TRADD和TNF受体相关因子2而非Fas相关死亡结构域，可阻止C20E介导的凋亡。JNK/p38 MAPK对B细胞淋巴瘤-2同源3相互作用结构域死亡激动剂（Bid）的切割将凋亡的外源性途径和线粒体途径联系起来。在进一步研究中，一种针对TNFR1细胞外结构域的抗体可阻止TNF-α诱导的凋亡，但不能阻止C20E诱导的凋亡。这些发现表明，C20E在细胞内作用于TNFR1，激活ASK1-MKK4/7-JNK/p38 MAPK信号传导，并促进Bid依赖性线粒体破坏和凋亡。在研究中，从携带MDA-MB-231异种移植瘤的C20E处理的裸鼠中分离出的肿瘤显示TUNEL染色增加，Ki67染色减少，分别反映凋亡增加和增殖减少。像C20E这样的ω-3-环氧脂肪酸可用于三阴性乳腺癌的治疗。-Dyari, H. R. E., Rawling, T., Chen, Y., Sudarmana, W., Bourget, K., Dwyer, J. M., Allison, S. E., Murray, M.一种新型ω-3 17,18-环氧二十碳四烯酸合成类似物激活TNF受体- /ASK1/JNK信号传导以促进人乳腺癌细胞凋亡 。
