HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

J. Biol. Chem., Vol. 280, Issue 36, 31413-31419, September 9, 2005

This Article Full Text Full Text (PDF) All Versions of this Article: 280/36/31413    most recent M500418200v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Nony, P. A. Articles by Roberts, J. D. Search for Related Content PubMed PubMed Citation Articles by Nony, P. A. Articles by Roberts, J. D. Social Bookmarking                      What's this?

15(S)-Lipoxygenase-2 Mediates Arachidonic Acid-stimulated Adhesion of Human Breast Carcinoma Cells through the Activation of TAK1, MKK6, and p38 MAPK^*

Paul A. Nony, Sarah B. Kennett, Wayne C. Glasgow¶, Kenneth Olden, and John D. Roberts||

From the Laboratory of Molecular Carcinogenesis, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina 27709 and the ^¶Division of Basic Medical Sciences, Mercer University School of Medicine, Macon, Georgia 31207

The dietary cis-polyunsaturated fatty acid, arachidonic acid, stimulates adhesion of metastatic human breast carcinoma cells (MDA-MB-435) to the extracellular matrix, but the molecular mechanisms by which fatty acids modify the behavior of these cells are unclear. Exposure to arachidonic acid activates multiple signaling pathways. Activation of p38 mitogen-activated protein kinase (p38 MAPK) is required for increased cell adhesion to type IV collagen, and this activation is sensitive to inhibitors of lipoxygenases, suggesting a requirement for arachidonic acid metabolism. The goals of the current study were to identify the one or more key metabolites of arachidonic acid that are responsible for activation of p38 MAPK and to elucidate the upstream kinases that lead to p38 MAPK activation. High performance liquid chromatographic analysis revealed that MDA-MB-435 cells metabolize exogenous arachidonic acid predominantly to 15(S)-hydroxyeicosatetraenoic acid (15(S)-HETE). Immunoblot analysis with antibodies specific to 15(S)-lipoxygenase-1 (LOX-1) and 15(S)-lipoxygenase-2 (LOX-2) demonstrated the expression of 15-LOX-2, but not 15-LOX-1, in these tumor cells. A LOX inhibitor, nordihydroguaiaretic acid, attenuated production of 15(S)-HETE and inhibited the phosphorylation of p38 MAPK following exposure to arachidonic acid. In contrast, overexpression of LOX-2 sensitized the cells to the addition of arachidonic acid, leading to increased activation of p38 MAPK. 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-₁-activated protein kinase-1 (TAK1) and MAPK kinase 6. Transfection of these cells with a dominant negative form of TAK1 blocked arachidonic acid-stimulated p38 MAPK phosphorylation. These data demonstrate that 15(S)-LOX-2 generation of 15(S)-HETE activates specific growth factor receptor-related signaling pathways, thereby initiating signal transduction events leading to increased cell adhesion to the extracellular matrix.

Received for publication, January 12, 2005 , and in revised form, May 31, 2005.

^* This research was supported by the Intramural Research Program of the NIEHS, National Institutes of Health. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Current Address: Center for Toxicology and Environmental Health, L.L.C., 615 West Markham, Little Rock, AR 72201.

^|| To whom correspondence should be addressed: Laboratory of Molecular Carcinogenesis, P. O. Box 12233, Mail Drop D2–05, NIEHS, National Institutes of Health, Research Triangle Park, NC 27709. Tel.: 919-541-5023; Fax: 919-541-0076; E-mail: roberts1{at}niehs.nih.gov.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				A. K. Bajpai, E. Blaskova, S. B. Pakala, T. Zhao, W. C. Glasgow, J. S. Penn, D. A. Johnson, and G. N. Rao 15(S)-HETE Production in Human Retinal Microvascular Endothelial Cells by Hypoxia: Novel Role for MEK1 in 15(S)-HETE Induced Angiogenesis Invest. Ophthalmol. Vis. Sci., November 1, 2007; 48(11): 4930 - 4938. [Abstract] [Full Text] [PDF]

				D. Schweiger, G. Furstenberger, and P. Krieg Inducible expression of 15-lipoxygenase-2 and 8-lipoxygenase inhibits cell growth via common signaling pathways J. Lipid Res., March 1, 2007; 48(3): 553 - 564. [Abstract] [Full Text] [PDF]

				G. Saavedra, W. Zhang, B. Peterson, and B. S. Cummings Differential Roles for Cytosolic and Microsomal Ca2+-Independent Phospholipase A2 in Cell Growth and Maintenance of Phospholipids J. Pharmacol. Exp. Ther., September 1, 2006; 318(3): 1211 - 1219. [Abstract] [Full Text] [PDF]