15-Lipoxygenase Metabolites of Docosahexaenoic Acid Inhibit Prostate Cancer Cell Proliferation and Survival

Abstract

A 15-LOX, it is proposed, suppresses the growth of prostate cancer in part by converting arachidonic, eicosatrienoic, and/or eicosapentaenoic acids to n-6 hydroxy metabolites. These metabolites inhibit the proliferation of PC3, LNCaP, and DU145 prostate cancer cells but only at ≥1–10 µM. We show here that the 15-LOX metabolites of docosahexaenoic acid (DHA), 17-hydroperoxy-, 17-hydroxy-, 10,17-dihydroxy-, and 7,17-dihydroxy-DHA inhibit the proliferation of these cells at ≥0.001, 0.01, 1, and 1 µM, respectively. By comparison, the corresponding 15-hydroperoxy, 15-hydroxy, 8,15-dihydroxy, and 5,15-dihydroxy metabolites of arachidonic acid as well as DHA itself require ≥10–100 µM to do this. Like DHA, the DHA metabolites a) induce PC3 cells to activate a peroxisome proliferator-activated receptor-γ (PPARγ) reporter, express syndecan-1, and become apoptotic and b) are blocked from slowing cell proliferation by pharmacological inhibition or knockdown of PPARγ or syndecan-1. The DHA metabolites thus slow prostate cancer cell proliferation by engaging the PPARγ/syndecan-1 pathway of apoptosis and thereby may contribute to the prostate cancer-suppressing effects of not only 15-LOX but also dietary DHA.

Lipidomic Profiling of Influenza Infection Identifies Mediators that Induce and Resolve Inflammation

“…Of note, several of these metabolites can be formed either enzymatically or through autoxidation processes. For example, 17-HDoHE is a putative product of the mammalian 12/15 LOX activity, which that can be further metabolized to protectin D1, a potential suppressor of viral replication (Morita et al, 2013; O’Flaherty et al, 2012). Similarly, other positional isoforms of hydroxylated DHA can be formed via 12/15 LOX (Morgan et al, 2010).…”

ω-3 Polyunsaturated fatty acids-derived lipid metabolites on angiogenesis, inflammation and cancer

“…EPA-derived 15-HEPE inhibited the formation of PGE 2 and 5-HETE, as well as cancer cell proliferation in PC-3 and LNCaP cells 67 . DHA-derived 17-HDHA inhibited the proliferation of prostate cancer cells (PC-3, LNCaP and DU145) at doses much lower than the corresponding metabolite of ARA (15-HETE) and DHA 68 . The other 15-LOX metabolites of DHA, including 17-hydroperoxy-, 10,17-dihydroxy- and 7,17-dihydroxy-DHA, also inhibited cell proliferation via mechanisms involving activation of PPAR-γ and syndecan-1 signaling in prostate cancer cells 68 .…”

“…DHA-derived 17-HDHA inhibited the proliferation of prostate cancer cells (PC-3, LNCaP and DU145) at doses much lower than the corresponding metabolite of ARA (15-HETE) and DHA 68 . The other 15-LOX metabolites of DHA, including 17-hydroperoxy-, 10,17-dihydroxy- and 7,17-dihydroxy-DHA, also inhibited cell proliferation via mechanisms involving activation of PPAR-γ and syndecan-1 signaling in prostate cancer cells 68 . The 15-LOX-mediated metabolism is required for the effect of DHA to induce syndecan-1 signaling and apoptosis in prostate cancer cells 69 .…”

Mammalian lipoxygenases and their biological relevance

“…Taken together, these data suggest a pro-carcinogenic character of this enzyme. On the other hand, ALOX15 -mediated metabolism of docosahexaenoic acid is required for apoptosis in prostate cancer cells [146] and ALOX15 metabolites of docosahexaenoic acid inhibit prostate cancer cell proliferation and cell survival [147]. Hence, in the presence of DHA the enzyme might exhibit anti-carcinogenic properties.…”