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-OXODHA 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.
To read the full publication, click HERE.
Date of publication : 11 January 2021; Scientific Reports (Nature Publisher Group); London Vol. 11, Iss. 1
Author Information: Kun‑Ming Chen (1), Henry Thompson (2), John P. Vanden‑Heuvel (3), Yuan‑Wan Sun (1), Neil Trushin (5), Cesar Aliaga (1), Krishne Gowda (4), Shantu Amin (4), Bruce Stanley (6), Andrea Manni (7), & Karam El‑Bayoumy (1)
(1) Department of Biochemistry and Molecular Biology, College of Medicine, Pennsylvania State University, Hershey, PA 17033, USA.
(2) Cancer Prevention Laboratory, Colorado State University, Fort Collins, CO 85023, USA.
(3) Department of Veterinary and Biomedical Sciences, Pennsylvania State University, University Park, PA 16802, USA.
(4) Department of Pharmacology, Pennsylvania State University College of Medicine, Hershey, PA 17033, USA.
(5) Department of Public Health Sciences, Pennsylvania State University College of Medicine, Hershey, PA 17033, USA.
(6) Mass Spectrometry and Proteomics Facility, College of Medicine, Pennsylvania State University, Hershey, PA 17033, USA.
(7) Department of Medicine, College of Medicine, Pennsylvania State University, Hershey, PA 17033, USA.