Skip to main content
PMC home page
Proceedings of the National Academy of Sciences of the United States of America logoLink to Proceedings of the National Academy of Sciences of the United States of America
. 1995 Sep 26;92(20):9323–9327. doi: 10.1073/pnas.92.20.9323

12(S)-hydroxyeicosatetraenoic acid and 13(S)-hydroxyoctadecadienoic acid regulation of protein kinase C-alpha in melanoma cells: role of receptor-mediated hydrolysis of inositol phospholipids.

B Liu 1, W A Khan 1, Y A Hannun 1, J Timar 1, J D Taylor 1, S Lundy 1, I Butovich 1, K V Honn 1
PMCID: PMC40977  PMID: 7568126

Abstract

Protein kinase C (PKC) isoenzymes are essential components of cell signaling. In this study, we investigated the regulation of PKC-alpha in murine B16 amelanotic melanoma (B16a) cells by the monohydroxy fatty acids 12(S)-hydroxyeicosatetraenoic acid [12(S)-HETE] and 13(S)-hydroxyoctadecadienoic acid [13(S)-HODE]. 12(S)-HETE induced a translocation of PKC-alpha to the plasma membrane and focal adhesion plaques, leading to enhanced adhesion of B16a cells to the matrix protein fibronectin. However, 13(S)-HODE inhibited these 12(S)-HETE effects on PKC-alpha. A receptor-mediated mechanism of action for 12(S)-HETE and 13(S)-HODE is supported by the following findings. First, 12(S)-HETE triggered a rapid increase in cellular levels of diacylglycerol and inositol trisphosphate in B16a cells. 13(S)-HODE blocked the 12(S)-HETE-induced bursts of both second messengers. Second, the 12(S)-HETE-increased adhesion of B16a cells to fibronectin was sensitive to inhibition by a phospholipase C inhibitor and pertussis toxin. Finally, a high-affinity binding site (Kd = 1 nM) for 12(S)-HETE was detected in B16a cells, and binding of 12(S)-HETE to B16a cells was effectively inhibited by 13(S)-HODE (IC50 = 4 nM). In summary, our data provide evidence that regulation of PKC-alpha by 12(S)-HETE and 13(S)-HODE may be through a guanine nucleotide-binding protein-linked receptor-mediated hydrolysis of inositol phospholipids.

Full text

PDF
9326

Images in this article

9324Fig. 1
on p.9324
9325Fig. 2
on p.9325
9326Fig. 3
on p.9326
9327Fig. 4
on p.9327

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. BLIGH E. G., DYER W. J. A rapid method of total lipid extraction and purification. Can J Biochem Physiol. 1959 Aug;37(8):911–917. doi: 10.1139/o59-099. [DOI] [PubMed] [Google Scholar]
  2. Blobe G. C., Sachs C. W., Khan W. A., Fabbro D., Stabel S., Wetsel W. C., Obeid L. M., Fine R. L., Hannun Y. A. Selective regulation of expression of protein kinase C (PKC) isoenzymes in multidrug-resistant MCF-7 cells. Functional significance of enhanced expression of PKC alpha. J Biol Chem. 1993 Jan 5;268(1):658–664. [PubMed] [Google Scholar]
  3. Fiore S., Ryeom S. W., Weller P. F., Serhan C. N. Lipoxin recognition sites. Specific binding of labeled lipoxin A4 with human neutrophils. J Biol Chem. 1992 Aug 15;267(23):16168–16176. [PubMed] [Google Scholar]
  4. Funk C. D., Furci L., FitzGerald G. A., Grygorczyk R., Rochette C., Bayne M. A., Abramovitz M., Adam M., Metters K. M. Cloning and expression of a cDNA for the human prostaglandin E receptor EP1 subtype. J Biol Chem. 1993 Dec 15;268(35):26767–26772. [PubMed] [Google Scholar]
  5. Gross E., Ruzicka T., von Restorff B., Stolz W., Klotz K. N. High-affinity binding and lack of growth-promoting activity of 12(S)-hydroxyeicosatetraenoic acid (12(S)-HETE) in a human epidermal cell line. J Invest Dermatol. 1990 Apr;94(4):446–451. doi: 10.1111/1523-1747.ep12874543. [DOI] [PubMed] [Google Scholar]
  6. Grossi I. M., Fitzgerald L. A., Umbarger L. A., Nelson K. K., Diglio C. A., Taylor J. D., Honn K. V. Bidirectional control of membrane expression and/or activation of the tumor cell IRGpIIb/IIIa receptor and tumor cell adhesion by lipoxygenase products of arachidonic acid and linoleic acid. Cancer Res. 1989 Feb 15;49(4):1029–1037. [PubMed] [Google Scholar]
  7. Hannun Y. A., Loomis C. R., Bell R. M. Activation of protein kinase C by Triton X-100 mixed micelles containing diacylglycerol and phosphatidylserine. J Biol Chem. 1985 Aug 25;260(18):10039–10043. [PubMed] [Google Scholar]
  8. Hansson A., Serhan C. N., Haeggström J., Ingelman-Sundberg M., Samuelsson B. Activation of protein kinase C by lipoxin A and other eicosanoids. Intracellular action of oxygenation products of arachidonic acid. Biochem Biophys Res Commun. 1986 Feb 13;134(3):1215–1222. doi: 10.1016/0006-291x(86)90380-3. [DOI] [PubMed] [Google Scholar]
  9. Herbertsson H., Hammarström S. High-affinity binding sites for 12(S)-hydroxy-5,8,10,14-eicosatetraenoic acid (12(S)-HETE) in carcinoma cells. FEBS Lett. 1992 Feb 24;298(2-3):249–252. doi: 10.1016/0014-5793(92)80069-s. [DOI] [PubMed] [Google Scholar]
  10. Hirata M., Hayashi Y., Ushikubi F., Yokota Y., Kageyama R., Nakanishi S., Narumiya S. Cloning and expression of cDNA for a human thromboxane A2 receptor. Nature. 1991 Feb 14;349(6310):617–620. doi: 10.1038/349617a0. [DOI] [PubMed] [Google Scholar]
  11. Honda A., Sugimoto Y., Namba T., Watabe A., Irie A., Negishi M., Narumiya S., Ichikawa A. Cloning and expression of a cDNA for mouse prostaglandin E receptor EP2 subtype. J Biol Chem. 1993 Apr 15;268(11):7759–7762. [PubMed] [Google Scholar]
  12. Honn K. V., Nelson K. K., Renaud C., Bazaz R., Diglio C. A., Timar J. Fatty acid modulation of tumor cell adhesion to microvessel endothelium and experimental metastasis. Prostaglandins. 1992 Nov;44(5):413–429. doi: 10.1016/0090-6980(92)90137-i. [DOI] [PubMed] [Google Scholar]
  13. Honn K. V., Tang D. G. Adhesion molecules and tumor cell interaction with endothelium and subendothelial matrix. Cancer Metastasis Rev. 1992 Nov;11(3-4):353–375. doi: 10.1007/BF01307187. [DOI] [PubMed] [Google Scholar]
  14. Honn K. V., Tang D. G., Grossi I. M., Renaud C., Duniec Z. M., Johnson C. R., Diglio C. A. Enhanced endothelial cell retraction mediated by 12(S)-HETE: a proposed mechanism for the role of platelets in tumor cell metastasis. Exp Cell Res. 1994 Jan;210(1):1–9. doi: 10.1006/excr.1994.1001. [DOI] [PubMed] [Google Scholar]
  15. Honn K. V., Tang D. G., Grossi I., Duniec Z. M., Timar J., Renaud C., Leithauser M., Blair I., Johnson C. R., Diglio C. A. Tumor cell-derived 12(S)-hydroxyeicosatetraenoic acid induces microvascular endothelial cell retraction. Cancer Res. 1994 Jan 15;54(2):565–574. [PubMed] [Google Scholar]
  16. Liu B., Renaud C., Nelson K. K., Chen Y. Q., Bazaz R., Kowynia J., Timar J., Diglio C. A., Honn K. V. Protein-kinase-C inhibitor calphostin C reduces B16 amelanotic melanoma cell adhesion to endothelium and lung colonization. Int J Cancer. 1992 Aug 19;52(1):147–152. doi: 10.1002/ijc.2910520126. [DOI] [PubMed] [Google Scholar]
  17. Liu B., Timar J., Howlett J., Diglio C. A., Honn K. V. Lipoxygenase metabolites of arachidonic and linoleic acids modulate the adhesion of tumor cells to endothelium via regulation of protein kinase C. Cell Regul. 1991 Dec;2(12):1045–1055. doi: 10.1091/mbc.2.12.1045. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. McPhail L. C., Clayton C. C., Snyderman R. A potential second messenger role for unsaturated fatty acids: activation of Ca2+-dependent protein kinase. Science. 1984 May 11;224(4649):622–625. doi: 10.1126/science.6231726. [DOI] [PubMed] [Google Scholar]
  19. Namba T., Oida H., Sugimoto Y., Kakizuka A., Negishi M., Ichikawa A., Narumiya S. cDNA cloning of a mouse prostacyclin receptor. Multiple signaling pathways and expression in thymic medulla. J Biol Chem. 1994 Apr 1;269(13):9986–9992. [PubMed] [Google Scholar]
  20. Nishizuka Y. Intracellular signaling by hydrolysis of phospholipids and activation of protein kinase C. Science. 1992 Oct 23;258(5082):607–614. doi: 10.1126/science.1411571. [DOI] [PubMed] [Google Scholar]
  21. Sakamoto K., Ezashi T., Miwa K., Okuda-Ashitaka E., Houtani T., Sugimoto T., Ito S., Hayaishi O. Molecular cloning and expression of a cDNA of the bovine prostaglandin F2 alpha receptor. J Biol Chem. 1994 Feb 4;269(5):3881–3886. [PubMed] [Google Scholar]
  22. Shearman M. S., Naor Z., Sekiguchi K., Kishimoto A., Nishizuka Y. Selective activation of the gamma-subspecies of protein kinase C from bovine cerebellum by arachidonic acid and its lipoxygenase metabolites. FEBS Lett. 1989 Jan 30;243(2):177–182. doi: 10.1016/0014-5793(89)80125-5. [DOI] [PubMed] [Google Scholar]
  23. Sjölander A., Grönroos E., Hammarström S., Andersson T. Leukotriene D4 and E4 induce transmembrane signaling in human epithelial cells. Single cell analysis reveals diverse pathways at the G-protein level for the influx and the intracellular mobilization of Ca2+. J Biol Chem. 1990 Dec 5;265(34):20976–20981. [PubMed] [Google Scholar]
  24. Smith R. J., Justen J. M., Nidy E. G., Sam L. M., Bleasdale J. E. Transmembrane signaling in human polymorphonuclear neutrophils: 15(S)-hydroxy-(5Z,8Z,11Z,13E)-eicosatetraenoic acid modulates receptor agonist-triggered cell activation. Proc Natl Acad Sci U S A. 1993 Aug 1;90(15):7270–7274. doi: 10.1073/pnas.90.15.7270. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Spector A. A., Gordon J. A., Moore S. A. Hydroxyeicosatetraenoic acids (HETEs). Prog Lipid Res. 1988;27(4):271–323. doi: 10.1016/0163-7827(88)90009-4. [DOI] [PubMed] [Google Scholar]
  26. Sugimoto Y., Namba T., Honda A., Hayashi Y., Negishi M., Ichikawa A., Narumiya S. Cloning and expression of a cDNA for mouse prostaglandin E receptor EP3 subtype. J Biol Chem. 1992 Apr 5;267(10):6463–6466. [PubMed] [Google Scholar]
  27. Süss R., Arenberger P., Gross E. C., Ruzicka T. Regulation of 12(S)-hydroxyeicosatetraenoic acid (12(S)-HETE) binding sites on human epidermal cells by interferon-gamma. Exp Cell Res. 1990 Dec;191(2):204–208. doi: 10.1016/0014-4827(90)90006-v. [DOI] [PubMed] [Google Scholar]
  28. Thompson A. K., Mostafapour S. P., Denlinger L. C., Bleasdale J. E., Fisher S. K. The aminosteroid U-73122 inhibits muscarinic receptor sequestration and phosphoinositide hydrolysis in SK-N-SH neuroblastoma cells. A role for Gp in receptor compartmentation. J Biol Chem. 1991 Dec 15;266(35):23856–23862. [PubMed] [Google Scholar]
  29. Timar J., Chen Y. Q., Liu B., Bazaz R., Taylor J. D., Honn K. V. The lipoxygenase metabolite 12(S)-HETE promotes alpha IIb beta 3 integrin-mediated tumor-cell spreading on fibronectin. Int J Cancer. 1992 Oct 21;52(4):594–603. doi: 10.1002/ijc.2910520418. [DOI] [PubMed] [Google Scholar]
  30. Watanabe T., Shimizu T., Miki I., Sakanaka C., Honda Z., Seyama Y., Teramoto T., Matsushima T., Ui M., Kurokawa K. Characterization of the guinea pig lung membrane leukotriene D4 receptor solubilized in an active form. Association and dissociation with an islet-activating protein-sensitive guanine nucleotide-binding protein. J Biol Chem. 1990 Dec 5;265(34):21237–21241. [PubMed] [Google Scholar]
  31. Wetsel W. C., Khan W. A., Merchenthaler I., Rivera H., Halpern A. E., Phung H. M., Negro-Vilar A., Hannun Y. A. Tissue and cellular distribution of the extended family of protein kinase C isoenzymes. J Cell Biol. 1992 Apr;117(1):121–133. doi: 10.1083/jcb.117.1.121. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Woods A., Couchman J. R. Protein kinase C involvement in focal adhesion formation. J Cell Sci. 1992 Feb;101(Pt 2):277–290. doi: 10.1242/jcs.101.2.277. [DOI] [PubMed] [Google Scholar]

Articles from Proceedings of the National Academy of Sciences of the United States of America are provided here courtesy of National Academy of Sciences

RESOURCES