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

Herryawan Ryadi Eziwar Dyari, Tristan Rawling, Yongjuan Chen, William Sudarmana, Kirsi Bourget, Julie M. Dwyer, Sarah E. Allison, Michael Murray

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)5246-5257
Number of pages12
JournalFASEB Journal
Volume31
Issue number12
DOIs
Publication statusPublished - 1 Jan 2017

Fingerprint

MAP Kinase Kinase Kinase 5
Tumor Necrosis Factor Receptors
Cells
Apoptosis
Breast Neoplasms
Acids
p38 Mitogen-Activated Protein Kinases
MAP Kinase Kinase Kinases
B-Cell Lymphoma
Chemical activation
Triple Negative Breast Neoplasms
Staining and Labeling
Death Domain Receptors
Eicosapentaenoic Acid
Epoxy Compounds
In Situ Nick-End Labeling
Cytochromes
Cytochromes c
Heterografts
Caspase 3

Keywords

  • Apoptotic signaling
  • Death receptor
  • Epoxyfatty acids

ASJC Scopus subject areas

  • Biotechnology
  • Biochemistry
  • Molecular Biology
  • Genetics

Cite this

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. / Eziwar Dyari, Herryawan Ryadi; Rawling, Tristan; Chen, Yongjuan; Sudarmana, William; Bourget, Kirsi; Dwyer, Julie M.; Allison, Sarah E.; Murray, Michael.

In: FASEB Journal, Vol. 31, No. 12, 01.01.2017, p. 5246-5257.

Research output: Contribution to journalArticle

Eziwar Dyari, Herryawan Ryadi ; Rawling, Tristan ; Chen, Yongjuan ; Sudarmana, William ; Bourget, Kirsi ; Dwyer, Julie M. ; Allison, Sarah E. ; Murray, Michael. / 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. In: FASEB Journal. 2017 ; Vol. 31, No. 12. pp. 5246-5257.
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AU - Chen, Yongjuan

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AU - Allison, Sarah E.

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