A novel synthetic analogue of v-3 17,18-epoxyeicosatetraenoic acid activates TNF receptor-1/ ASK1/JNK signaling to promote apoptosis in human breast cancer cells

Dyari, HRE; Rawling, T; Chen, Y; Sudarmana, W; Bourget, K; Dwyer, JM; Allison, SE; Murray, M

A novel synthetic analogue of v-3 17,18-epoxyeicosatetraenoic acid activates TNF receptor-1/ ASK1/JNK signaling to promote apoptosis in human breast cancer cells

Dyari, HRE Rawling, T

Chen, Y Sudarmana, W Bourget, K Dwyer, JM Allison, SE Murray, M

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Publication Type:: Journal Article
Citation:: FASEB Journal, 2017, 31 (12), pp. 5246 - 5257
Issue Date:: 2017-01-01

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Field	Value	Language
dc.contributor.author	Dyari, HRE	en_US
dc.contributor.author	Rawling, T https://orcid.org/0000-0002-6624-6586	en_US
dc.contributor.author	Chen, Y	en_US
dc.contributor.author	Sudarmana, W	en_US
dc.contributor.author	Bourget, K	en_US
dc.contributor.author	Dwyer, JM	en_US
dc.contributor.author	Allison, SE	en_US
dc.contributor.author	Murray, M	en_US
dc.date.available	2017-07-25	en_US
dc.date.issued	2017-01-01	en_US
dc.identifier.citation	FASEB Journal, 2017, 31 (12), pp. 5246 - 5257	en_US
dc.identifier.issn	0892-6638	en_US
dc.identifier.uri	http://hdl.handle.net/10453/123135
dc.description.abstract	© FASEB A saturated analog of the cytochrome P450–mediated v-3-17,18-epoxide of v-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-a 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 in vivo 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. v-3-Epoxy fatty acids like C20E could be incorporated into treatments for triple-negative breast cancers.	en_US
dc.relation	http://purl.org/au-research/grants/nhmrc/GNT1087248
dc.relation.ispartof	FASEB Journal	en_US
dc.relation.isbasedon	10.1096/fj.201700033R	en_US
dc.subject.classification	Biochemistry & Molecular Biology	en_US
dc.subject.mesh	Cell Line, Tumor	en_US
dc.subject.mesh	Animals	en_US
dc.subject.mesh	Mice, Inbred BALB C	en_US
dc.subject.mesh	Humans	en_US
dc.subject.mesh	Mice	en_US
dc.subject.mesh	Breast Neoplasms	en_US
dc.subject.mesh	MAP Kinase Kinase Kinase 5	en_US
dc.subject.mesh	JNK Mitogen-Activated Protein Kinases	en_US
dc.subject.mesh	p38 Mitogen-Activated Protein Kinases	en_US
dc.subject.mesh	Arachidonic Acids	en_US
dc.subject.mesh	Tumor Necrosis Factor-alpha	en_US
dc.subject.mesh	Receptors, Tumor Necrosis Factor	en_US
dc.subject.mesh	Receptors, Tumor Necrosis Factor, Type I	en_US
dc.subject.mesh	Apoptosis	en_US
dc.subject.mesh	Female	en_US
dc.subject.mesh	Caspase 3	en_US
dc.subject.mesh	Receptors, TNF-Related Apoptosis-Inducing Ligand	en_US
dc.subject.mesh	TNF Receptor-Associated Death Domain Protein	en_US
dc.subject.mesh	fas Receptor	en_US
dc.title	A novel synthetic analogue of v-3 17,18-epoxyeicosatetraenoic acid activates TNF receptor-1/ ASK1/JNK signaling to promote apoptosis in human breast cancer cells	en_US
dc.type	Journal Article
utslib.citation.volume	12	en_US
utslib.citation.volume	31	en_US
utslib.for	0601 Biochemistry and Cell Biology	en_US
utslib.for	0606 Physiology	en_US
utslib.for	1116 Medical Physiology	en_US
pubs.embargo.period	Not known	en_US
pubs.organisational-group	/University of Technology Sydney
pubs.organisational-group	/University of Technology Sydney/Faculty of Science
pubs.organisational-group	/University of Technology Sydney/Faculty of Science/School of Mathematical and Physical Sciences
utslib.copyright.status	closed_access
pubs.issue	12	en_US
pubs.publication-status	Published	en_US
pubs.volume	31	en_US

Abstract:

© FASEB A saturated analog of the cytochrome P450–mediated v-3-17,18-epoxide of v-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-a 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 in vivo 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. v-3-Epoxy fatty acids like C20E could be incorporated into treatments for triple-negative breast cancers.

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http://hdl.handle.net/10453/123135