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Chemical Compound Review

Icomucret     (5Z,8Z,11Z,13E,15S)-15- hydroxyicosa-5,8,11...

Synonyms: AC1NQXHT, CHEMBL594621, CHEMBL1907680, BSPBio_001337, CHEBI:15558, ...
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Disease relevance of 15S-HETE

  • We therefore believe that in unstimulated cells Bcl-x(L) and Bax form a heterodimer, in which Bcl-x(L) dominates and prevents the induction of apoptosis, whereas in IL-4-stimulated cells the 15(S)-HETE/PPARgamma complex down-regulates Bcl-x(L), and the resulting overweight of Bax commits the cell to apoptosis via caspase-3 [1].
  • We have previously demonstrated that rat Walker 256 (W256) carcinosarcoma cells express the platelet-type 12-lipoxygenase (12-LOX) and synthesize 12(S)- and 15(S)-HETE as their major LOX metabolites [2].
  • The levels of both soluble and cell-associated 15(S)-HETE resulted significantly higher in chronic bronchitis than in control subjects [3].
  • CONCLUSION: The data suggest that severe asthmatics with persistent airway eosinophils manifest high levels of 15(S)-HETE in BALF, which may be associated with airway fibrosis [4].

High impact information on 15S-HETE

  • The enhanced 5-lipoxygenase activation of blood PMN from asthmatics and the metabolism of exogenous 15(S)-HETE may reflect a priming induced by various mediators released from environmental cells, and could be considered as a model of transcellular signalization between PMN and endothelial cells [5].
  • 15-HETE levels are frequently elevated at sites of inflammation, and extracellular 15(S)-HETE is esterified rapidly into neutrophil (PMN) phospholipids in vitro to levels that are comparable with arachidonic acid [6].
  • As a result of these actions, esterified 15(S)-HETE attenuates the cytoskeletal rearrangements and CD11/CD18-mediated adhesive events that subserve directed locomotion of PMN across endothelium [6].
  • In the absence of IL-4, major eicosanoids of CD34(+)-derived DCs were 5S-hydroxyeicosatetraenoic acid (5S-HETE) and leukotriene B(4), whereas the major eicosanoids of IL-4-treated DCs were 15S-HETE and 5S-15S-diHETE [7].
  • 15(S)-HETE stimulated Akt and S6K1 phosphorylation in HDMVEC in a time-dependent manner [8].

Biological context of 15S-HETE


Anatomical context of 15S-HETE

  • We investigated the expression of peroxisome proliferator-activated receptor (PPAR) gamma in benign and malignant prostate tissues and the ability of 15S-HETE to activate PPARgamma-dependent transcription and modulate proliferation of the Pca cell line PC3 [10].
  • After passive sensitization with human IgE and anti-IgE challenge, IL-4-stimulated monocytes released higher amounts of 15(S)-HETE than IL-4-unstimulated monocytes (P <.02) [12].
  • OBJECTIVE: Our purpose was to evaluate the levels of both soluble and cell-associated 15(S)-HETE and to examine 15-lipoxygenase (15-LO) messenger RNA (mRNA) expression in sputum samples obtained from 10 control and 18 asthmatic subjects [13].
  • Pretreatment with the anti-human B-cell CD23 MHM6 mAb caused a dose-dependent inhibition of 15(S)-HETE release [12].
  • Interleukin-4 enhances 15-lipoxygenase activity and incorporation of 15(S)-HETE into cellular phospholipids in cultured pulmonary epithelial cells [14].

Associations of 15S-HETE with other chemical compounds

  • We also demonstrate that FLAP can stimulate (2-2.5-fold) the oxygenation of 15(S)-HETE by 5-LO to 5,15-diHETE [15].
  • Chiral phase high performance liquid chromatography analysis showed that aspirin-treated hPGHS-2 produced 15(R)-HETE, with no detectable 15(S)-HETE [16].
  • Moreover, we report that 5-HETE, 12(S)-HETE, and 15(S)-HETE are mitogenic on 3T6 fibroblast in the absence of another growth factor, and this effect was dependent on the activation of the phosphatidylinositol-3-kinase pathway [17].
  • (iii) Introduction of a bulky glycerol moiety at the carboxylic group of 15S-HETE reversed the kinetic effects of methylation and led to a 14R-oxygenation of the substrate [18].
  • It was observed that 12(S)- and 15(S)-HETE and 13(S)-HODE (12- and 15-lipoxygenase-derived metabolites, respectively) inhibited the 5-lipoxygenase present in rat basophilic leukemia (RBL-1) cell homogenates whereas the 15(R) chiral enantiomer and the nonhydroxylated linoleic, oleic, and stearic acids were either less potent or ineffective [19].

Gene context of 15S-HETE

  • Characterization of human ocular mucin secretion mediated by 15(S)-HETE [20].
  • Pretreatment with the 15-lipoxygenase metabolite, 15(S)-hydroxyeicosatetraenoic acid (15(S)-HETE), followed by EGF or HGF, produced faster translocation of PKCalpha detectable at 2 min [11].
  • Addition of exogenous 15(S)-HETE to MDA-MB-435 cells stimulated cell adhesion to type IV collagen and activated the p38 MAPK pathway, including the upstream kinases transforming growth factor-beta1-activated protein kinase-1 (TAK1) and MAPK kinase 6 [21].
  • These results support the hypothesis that 15-LOX-2-derived 15S-HETE may constitute an endogenous ligand for PPARgamma in the prostate and that loss of this pathway by reduced expression of 15-LOX-2 may contribute to increased proliferation and reduced differentiation in prostate carcinoma [10].
  • The latter was accomplished by the interaction of the 15(S)-HETE/PPARgamma complex with the adapter protein Fas-associating protein with death domain and caspase-8, as shown by transfection of Fas-associating protein with death domain dominant negative vector and cleavage of caspase 8 to active subunits p41/42 and p18 [1].

Analytical, diagnostic and therapeutic context of 15S-HETE


  1. IL-4 induces apoptosis in A549 lung adenocarcinoma cells: evidence for the pivotal role of 15-hydroxyeicosatetraenoic acid binding to activated peroxisome proliferator-activated receptor gamma transcription factor. Shankaranarayanan, P., Nigam, S. J. Immunol. (2003) [Pubmed]
  2. Overexpression of leukocyte-type 12-lipoxygenase promotes W256 tumor cell survival by enhancing alphavbeta5 expression. Pidgeon, G.P., Tang, K., Rice, R.L., Zacharek, A., Li, L., Taylor, J.D., Honn, K.V. Int. J. Cancer (2003) [Pubmed]
  3. 15(S)-HETE modulates LTB(4) production and neutrophil chemotaxis in chronic bronchitis. Profita, M., Sala, A., Riccobono, L., Pace, E., Paternò, A., Zarini, S., Siena, L., Mirabella, A., Bonsignore, G., Vignola, A.M. Am. J. Physiol., Cell Physiol. (2000) [Pubmed]
  4. Expression and activation of 15-lipoxygenase pathway in severe asthma: relationship to eosinophilic phenotype and collagen deposition. Chu, H.W., Balzar, S., Westcott, J.Y., Trudeau, J.B., Sun, Y., Conrad, D.J., Wenzel, S.E. Clin. Exp. Allergy (2002) [Pubmed]
  5. 5(S),15(S)-dihydroxyeicosatetraenoic acid and lipoxin generation in human polymorphonuclear cells: dual specificity of 5-lipoxygenase towards endogenous and exogenous precursors. Chavis, C., Vachier, I., Chanez, P., Bousquet, J., Godard, P. J. Exp. Med. (1996) [Pubmed]
  6. Remodeling of neutrophil phospholipids with 15(S)-hydroxyeicosatetraenoic acid inhibits leukotriene B4-induced neutrophil migration across endothelium. Takata, S., Matsubara, M., Allen, P.G., Janmey, P.A., Serhan, C.N., Brady, H.R. J. Clin. Invest. (1994) [Pubmed]
  7. IL-4 determines eicosanoid formation in dendritic cells by down-regulation of 5-lipoxygenase and up-regulation of 15-lipoxygenase 1 expression. Spanbroek, R., Hildner, M., Köhler, A., Müller, A., Zintl, F., Kühn, H., Rådmark, O., Samuelsson, B., Habenicht, A.J. Proc. Natl. Acad. Sci. U.S.A. (2001) [Pubmed]
  8. 15(S)-hydroxyeicosatetraenoic acid induces angiogenesis via activation of PI3K-Akt-mTOR-S6K1 signaling. Zhang, B., Cao, H., Rao, G.N. Cancer Res. (2005) [Pubmed]
  9. Mechanisms controlling cell cycle arrest and induction of apoptosis after 12-lipoxygenase inhibition in prostate cancer cells. Pidgeon, G.P., Kandouz, M., Meram, A., Honn, K.V. Cancer Res. (2002) [Pubmed]
  10. 15S-Hydroxyeicosatetraenoic acid activates peroxisome proliferator-activated receptor gamma and inhibits proliferation in PC3 prostate carcinoma cells. Shappell, S.B., Gupta, R.A., Manning, S., Whitehead, R., Boeglin, W.E., Schneider, C., Case, T., Price, J., Jack, G.S., Wheeler, T.M., Matusik, R.J., Brash, A.R., Dubois, R.N. Cancer Res. (2001) [Pubmed]
  11. Epidermal and hepatocyte growth factors, but not keratinocyte growth factor, modulate protein kinase Calpha translocation to the plasma membrane through 15(S)-hydroxyeicosatetraenoic acid synthesis. Sharma, G.D., Ottino, P., Bazan, N.G., Bazan, H.E. J. Biol. Chem. (2005) [Pubmed]
  12. IL-4 and IgE-anti-IgE modulation of 15(S)-hydroxyeicosatetraenoic acid release by mononuclear phagocytes. Profita, M., Vignola, A.M., Mirabella, A., Siena, L., Sala, A., Gjomarkaj, M., Bousquet, J., Bonsignore, G. J. Allergy Clin. Immunol. (1999) [Pubmed]
  13. 15-Lipoxygenase expression and 15(S)-hydroxyeicoisatetraenoic acid release and reincorporation in induced sputum of asthmatic subjects. Profita, M., Sala, A., Riccobono, L., Paternò, A., Mirabella, A., Bonanno, A., Guerrera, D., Pace, E., Bonsignore, G., Bousquet, J., Vignola, A.M. J. Allergy Clin. Immunol. (2000) [Pubmed]
  14. Interleukin-4 enhances 15-lipoxygenase activity and incorporation of 15(S)-HETE into cellular phospholipids in cultured pulmonary epithelial cells. Profita, M., Vignola, A.M., Sala, A., Mirabella, A., Siena, L., Pace, E., Folco, G., Bonsignore, G. Am. J. Respir. Cell Mol. Biol. (1999) [Pubmed]
  15. Cellular oxygenation of 12-hydroxyeicosatetraenoic acid and 15-hydroxyeicosatetraenoic acid by 5-lipoxygenase is stimulated by 5-lipoxygenase-activating protein. Mancini, J.A., Waterman, H., Riendeau, D. J. Biol. Chem. (1998) [Pubmed]
  16. Overexpression of human prostaglandin G/H synthase-1 and -2 by recombinant vaccinia virus: inhibition by nonsteroidal anti-inflammatory drugs and biosynthesis of 15-hydroxyeicosatetraenoic acid. O'Neill, G.P., Mancini, J.A., Kargman, S., Yergey, J., Kwan, M.Y., Falgueyret, J.P., Abramovitz, M., Kennedy, B.P., Ouellet, M., Cromlish, W. Mol. Pharmacol. (1994) [Pubmed]
  17. Hydroxyeicosatetraenoic acids released through the cytochrome P-450 pathway regulate 3T6 fibroblast growth. Nieves, D., Moreno, J.J. J. Lipid Res. (2006) [Pubmed]
  18. Probing the substrate alignment at the active site of 15-lipoxygenases by targeted substrate modification and site-directed mutagenesis. Evidence for an inverse substrate orientation. Schwarz, K., Borngräber, S., Anton, M., Kuhn, H. Biochemistry (1998) [Pubmed]
  19. Mono (S) hydroxy fatty acids: novel ligands for cytosolic actin. Kang, L.T., Vanderhoek, J.Y. J. Lipid Res. (1998) [Pubmed]
  20. Characterization of human ocular mucin secretion mediated by 15(S)-HETE. Jumblatt, J.E., Cunningham, L.T., Li, Y., Jumblatt, M.M. Cornea (2002) [Pubmed]
  21. 15S-Lipoxygenase-2 mediates arachidonic acid-stimulated adhesion of human breast carcinoma cells through the activation of TAK1, MKK6, and p38 MAPK. Nony, P.A., Kennett, S.B., Glasgow, W.C., Olden, K., Roberts, J.D. J. Biol. Chem. (2005) [Pubmed]
  22. Detection and subcellular localization of two 15S-lipoxygenases in human cornea. Chang, M.S., Schneider, C., Roberts, R.L., Shappell, S.B., Haselton, F.R., Boeglin, W.E., Brash, A.R. Invest. Ophthalmol. Vis. Sci. (2005) [Pubmed]
  23. Generation of eicosanoids from 15(S)-hydroxyeicosatetraenoic acid in blood monocytes from steroid-dependent asthmatic patients. Chavis, C., Vachier, I., Bousquet, J., Godard, P., Chanez, P. Biochem. Pharmacol. (1998) [Pubmed]
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