Lipoxygenase catalyzed metabolites derived from docosahexaenoic acid are promising antitumor agents against breast cancer

Abstract Docosahexaenoic acid (DHA) is known to inhibit breast cancer in the rat. Here we investigated whether DHA itself or select metabolites can account for its antitumor action. We focused on metabolites derived from the lipoxygenase (LOX) pathway since we previously showed that they were superi...

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Autores principales:	Kun-Ming Chen, Henry Thompson, John P. Vanden-Heuvel, Yuan-Wan Sun, Neil Trushin, Cesar Aliaga, Krishne Gowda, Shantu Amin, Bruce Stanley, Andrea Manni, Karam El-Bayoumy
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/c4bb46a811624f08af671d39c0e3ef81
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spelling	oai:doaj.org-article:c4bb46a811624f08af671d39c0e3ef812021-12-02T14:12:45ZLipoxygenase catalyzed metabolites derived from docosahexaenoic acid are promising antitumor agents against breast cancer10.1038/s41598-020-79716-x2045-2322https://doaj.org/article/c4bb46a811624f08af671d39c0e3ef812021-01-01T00:00:00Zhttps://doi.org/10.1038/s41598-020-79716-xhttps://doaj.org/toc/2045-2322Abstract Docosahexaenoic acid (DHA) is known to inhibit breast cancer in the rat. Here we investigated whether DHA itself or select metabolites can account for its antitumor action. We focused on metabolites derived from the lipoxygenase (LOX) pathway since we previously showed that they were superior anti-proliferating agents compared to DHA; 4-OXO-DHA was the most potent. A lipidomics approach detected several LOX-metabolites in plasma and the mammary gland in rats fed DHA; we also identified for the first time, 4-OXO-DHA in rat plasma. In a reporter assay, 4-OXO-DHA and 4-HDHA were more effective activators of PPARɣ than DHA. In breast cancer cell lines, 4-OXO-DHA induced PPARɣ and 15-hydroxyprostaglandin dehydrogenase (15-PGDH) but inhibited the activity of NF-κB and suppressed PI3K and mTOR signaling. Because of the structural characteristics of 4-OXO-DHA (Michael acceptor), not shared by any of the other hydroxylated-DHA, we used MS and showed that it can covalently modify the cysteine residue of NF-κB. We have also shown that the chemopreventive effect of DHA is associated with significant reduction of PGE2 levels, in both rat mammary tumors induced by MNU and non-involved mammary tissues. Collectively, our results indicate that 4-OXO-DHA is the metabolite of choice in future chemoprevention studies.Kun-Ming ChenHenry ThompsonJohn P. Vanden-HeuvelYuan-Wan SunNeil TrushinCesar AliagaKrishne GowdaShantu AminBruce StanleyAndrea ManniKaram El-BayoumyNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-10 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Kun-Ming Chen Henry Thompson John P. Vanden-Heuvel Yuan-Wan Sun Neil Trushin Cesar Aliaga Krishne Gowda Shantu Amin Bruce Stanley Andrea Manni Karam El-Bayoumy Lipoxygenase catalyzed metabolites derived from docosahexaenoic acid are promising antitumor agents against breast cancer
description	Abstract Docosahexaenoic acid (DHA) is known to inhibit breast cancer in the rat. Here we investigated whether DHA itself or select metabolites can account for its antitumor action. We focused on metabolites derived from the lipoxygenase (LOX) pathway since we previously showed that they were superior anti-proliferating agents compared to DHA; 4-OXO-DHA was the most potent. A lipidomics approach detected several LOX-metabolites in plasma and the mammary gland in rats fed DHA; we also identified for the first time, 4-OXO-DHA in rat plasma. In a reporter assay, 4-OXO-DHA and 4-HDHA were more effective activators of PPARɣ than DHA. In breast cancer cell lines, 4-OXO-DHA induced PPARɣ and 15-hydroxyprostaglandin dehydrogenase (15-PGDH) but inhibited the activity of NF-κB and suppressed PI3K and mTOR signaling. Because of the structural characteristics of 4-OXO-DHA (Michael acceptor), not shared by any of the other hydroxylated-DHA, we used MS and showed that it can covalently modify the cysteine residue of NF-κB. We have also shown that the chemopreventive effect of DHA is associated with significant reduction of PGE2 levels, in both rat mammary tumors induced by MNU and non-involved mammary tissues. Collectively, our results indicate that 4-OXO-DHA is the metabolite of choice in future chemoprevention studies.
format	article
author	Kun-Ming Chen Henry Thompson John P. Vanden-Heuvel Yuan-Wan Sun Neil Trushin Cesar Aliaga Krishne Gowda Shantu Amin Bruce Stanley Andrea Manni Karam El-Bayoumy
author_facet	Kun-Ming Chen Henry Thompson John P. Vanden-Heuvel Yuan-Wan Sun Neil Trushin Cesar Aliaga Krishne Gowda Shantu Amin Bruce Stanley Andrea Manni Karam El-Bayoumy
author_sort	Kun-Ming Chen
title	Lipoxygenase catalyzed metabolites derived from docosahexaenoic acid are promising antitumor agents against breast cancer
title_short	Lipoxygenase catalyzed metabolites derived from docosahexaenoic acid are promising antitumor agents against breast cancer
title_full	Lipoxygenase catalyzed metabolites derived from docosahexaenoic acid are promising antitumor agents against breast cancer
title_fullStr	Lipoxygenase catalyzed metabolites derived from docosahexaenoic acid are promising antitumor agents against breast cancer
title_full_unstemmed	Lipoxygenase catalyzed metabolites derived from docosahexaenoic acid are promising antitumor agents against breast cancer
title_sort	lipoxygenase catalyzed metabolites derived from docosahexaenoic acid are promising antitumor agents against breast cancer
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/c4bb46a811624f08af671d39c0e3ef81
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Lipoxygenase catalyzed metabolites derived from docosahexaenoic acid are promising antitumor agents against breast cancer

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