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

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

doi:10.1074/jbc.m500418200

Cited by 53 publications

(50 citation statements)

References 45 publications

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“…Furthermore, decreased arachidonic acid-containing phospholipids, paired with decreases in the enzyme responsible for arachidonic acid release, may result in the overall inhibition of cell growth. In either scenario, once released arachidonic acid could facilitate cell growth through a number of well established mechanisms, including activation of epidermal growth factor receptors (Choudhury et al, 2000) or activation of kinase signaling cascades (Nony et al, 2005). The decrease in phospholipids induced by iPLA 2 ␤ inhibition is probably caused by a decreased role of this enzyme in the Land's cycle as shown others (Balsinde et al, 1997a).…”

Section: Discussionmentioning

confidence: 99%

Differential Roles for Cytosolic and Microsomal Ca²⁺-Independent Phospholipase A₂in Cell Growth and Maintenance of Phospholipids

Saavedra¹,

Zhang²,

Peterson³

et al. 2006

J Pharmacol Exp Ther

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Physiological roles of microsomal (iPLA 2 ␥) and cytosolic (iPLA 2 ␤) Ca 2ϩ -independent phospholipase A 2 were determined in two different epithelial cell models. R-and S-enantiomers of the iPLA 2 inhibitor bromoenol lactone (BEL) were isolated and shown to selectively inhibit iPLA 2␥ and iPLA 2␤ , respectively. The effect of these enantiomers on cell growth was assessed in human embryonic kidney 293 and Caki-1 cells using 3-(4-dimethylthiazolyl-2)-2,5-diphenyltetrazolium bromide (MTT). S-BEL (0 -5.0 M) decreased MTT staining 35% after 24 h compared with control cells, whereas treatment with either R-BEL or R/S-BEL induced 15% decreases. Neither R-BEL nor S-BEL induced cell death as determined by annexin V and propidium iodide staining. Transfection of cells with iPLA 2 ␤ siRNA reduced MTT staining approximately 35%, whereas transfection of cells with iPLA 2 ␥ siRNA only decreased MTT staining 10 to 15% compared with control cells. The effect of iPLA 2 ␤ and iPLA 2 ␥ siRNA on cell number and protein was also determined, and iPLA 2 ␤ siRNA decreased cell number and protein 25% compared with control cells. In contrast, iPLA 2 ␥ siRNA decreased cell number, but not cellular protein, compared with control cells. Selective inhibition of iPLA 2 ␤, but not iPLA 2 ␥, decreased several arachidonic acid-containing phospholipids, including 16:1-20:4, 16:0-20:4, 18:1-20:4, and 18:0-20:4 phosphatidylcholine, showing that the ability of iPLA 2 ␤ inhibitors to decrease cell growth correlates with their ability to decrease arachidonic acid-containing phospholipids. These data show that iPLA 2 ␤ inhibition results in greater decreases in cell growth and proliferation than iPLA 2 ␥, identifies specific phospholipids whose expressions are differentially regulated by iPLA 2 ␤ and iPLA 2 ␥, and suggests novel roles for iPLA 2 ␤ in cell growth.

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Section: Discussionmentioning

confidence: 99%

Differential Roles for Cytosolic and Microsomal Ca²⁺-Independent Phospholipase A₂in Cell Growth and Maintenance of Phospholipids

Saavedra¹,

Zhang²,

Peterson³

et al. 2006

J Pharmacol Exp Ther

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“…The arachidonic acid metabolites were eluted with 100% methanol followed by evaporation to dryness. The metabolites were reconstituted in 50 l of 100% methanol and analyzed by reverse-phase high performance liquid chromatography using a C18 column (5-m particle size, 4.6 ϫ 250 mm, Beckman Instruments, Berkeley, CA) as described previously using methanol:water:acetic acid with 55:45:0.01 and 75:25:0.01 ratios and 100% methanol as the mobile phases at a flow rate of 1.0 ml/min for 40, 30, and 20 min (31).…”

Section: (S)-hete (34230) 12(s)-hete (34570) 15(s)-hete (34720) Amentioning

confidence: 99%

Src-dependent STAT-3-mediated Expression of Monocyte Chemoattractant Protein-1 Is Required for 15(S)-Hydroxyeicosatetraenoic Acid-induced Vascular Smooth Muscle Cell Migration

Potula

Wang

Quyền

et al. 2009

Journal of Biological Chemistry

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VSMC3 migration from media to intima plays a determinant role in atherosclerosis and restenosis (1-3). Arachidonic acid (AA) and its oxygenated metabolites, collectively known as eicosanoids, are involved in the maintenance of vascular tone (4, 5). Lipoxygenases (LOXs) are non-heme iron dioxygenases that stereospecifically introduce molecular oxygen into polyunsaturated fatty acids, resulting in the formation of hydroperoxyeicosatetraenoic acids, which are subsequently converted to hydroxyeicosatetraenoic acids (HETEs) (6). Two 15-LOXs, namely, 15-LOX1 and 15-LOX2, have been shown to be expressed in humans (7,8). Both enzymes metabolize linoleic acid to 13(S)-hydroperoxyoctadecadienoic acid and AA to 15(S)-hydroperoxyeicosatetraenoic acid preferentially (9, 10). In regard to their tissue distribution, whereas 15-LOX1 shows a narrow cell-specific expression, including human reticulocytes and airway epithelial cells, 15-LOX2 appears to be expressed in epithelial cell types in cornea, lung, prostate, and skin (11). The studies from our laboratory showed that both 15-LOX1 and 15-LOX2 are expressed in human retinal microvascular endothelial cells (12). Although the presence of 15-LOX2 in VSMC has yet to be reported, these cells express 15-LOX1 (also known as 12/15-LOX in murines) and, when exposed to AA, produce both 15(S)-HETE and 12(S)-HETE (13,14). It is also known that 15-LOX1 and 12/15-LOX are involved in the oxidation of low density lipoprotein, a contributing factor in the pathogenesis of atherosclerosis (15, 16). Furthermore, using either transgenic or knock-out mice models, a number of studies have demonstrated that 15-LOX1 and its murine ortholog 12/15-LOX play a role in atherosclerosis and restenosis (17)(18)(19). In addition, human atheroma homogenates upon incubation with AA converted it mainly to .In recent years LOX products of polyunsaturated fatty acids have also been shown to be potent chemoattractants for resi-* This work was supported, in whole or in part, by National Institutes of Health Grant HL064165 (NHLBI; to G. N. R.

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“…Inhibition of p38 MAPK activation blocked cell adhesion as did functionblocking antibodies specific for subunits of the collagen receptor (40). More recently, we identified the key metabolite of AA (15-(S)-hydroxyeicosatetraenoic acid) and the upstream kinases (TAK1 and MKK6) that are responsible for activation of p38 MAPK in this system (41).…”

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confidence: 99%

Arachidonic Acid Stimulates Cell Adhesion through a Novel p38 MAPK-RhoA Signaling Pathway That Involves Heat Shock Protein 27

Garcia

Ray

Lackford

et al. 2009

Journal of Biological Chemistry

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Rho GTPases are critical components of cellular signal transduction pathways. Both hyperactivity and overexpression of these proteins have been observed in human cancers and have been implicated as important factors in metastasis. We previously showed that dietary n-6 fatty acids increase cancer cell adhesion to extracellular matrix proteins, such as type IV collagen. Here we report that in MDA-MB-435 human melanoma cells, arachidonic acid activates RhoA, and inhibition of RhoA signaling with either C3 exoenzyme or dominant negative Rho blocked arachidonic acid-induced cell adhesion. Inhibition of the Rho kinase (ROCK) with either small molecule inhibitors or ROCK II-specific small interfering RNA (siRNA) blocked the fatty acid-induced adhesion. However, unlike other systems, inhibition of ROCK did not block the activation of p38 mitogenactivated protein kinase (MAPK); instead, Rho activation depended on p38 MAPK activity and the presence of heat shock protein 27 (HSP27), which is phosphorylated downstream of p38 after arachidonic acid treatment. HSP27 associated with p115RhoGEF in fatty acid-treated cells, and this association was blocked when p38 was inhibited. Furthermore, siRNA knockdown of HSP27 blocked the fatty acid-stimulated Rho activity. Expression of dominant negative p115-RhoGEF or p115RhoGEF-specific siRNA inhibited both RhoA activation and adhesion on type IV collagen, whereas a constitutively active p115RhoGEF restored the arachidonic acid stimulation in cells in which the p38 MAPK had been inhibited. These data suggest that n-6 dietary fatty acids stimulate a set of interactions that regulates cell adhesion through RhoA and ROCK II via a p38 MAPK-dependent association of HSP27 and p115RhoGEF.The ability of tumor cells to metastasize to secondary sites is a hallmark of neoplastic disease. Unfortunately, this propensity to spread is the primary cause of morbidity and death in cancer patients (1). Metastasis is clearly a highly regulated, multistep process that occurs in a spatiotemporal manner (2-4). To escape the restrictive compartment boundaries characteristic of adult tissue, separate intravasation and extravasation steps requiring alterations in co-adhesion, adhesion, invasion, and migration must occur. Execution of these biological processes, involving multiple proteins and cellular organelles, require highly coordinated cell signaling mechanisms.The Rho family of small GTPases regulates many facets of cytoskeletal rearrangements that facilitate cell attachment and migration (5-7). Rho GTPases act as molecular switches by changing from an inactive GDP-bound conformation to an active GTPbound conformation, thereby regulating a signaling pathway. These proteins are directly regulated by Rho guanine nucleotide exchange factors (GEFs), 2 Rho GTPase activating proteins, and Rho GDP-dissociation inhibitors (8 -12). RhoGEFs bind to the GTPase to catalyze the dissociation of GDP, allowing the binding of GTP and thereby promoting Rho activation (8). The RGS (regulators of G protein signaling) domain-c...

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

Cited by 53 publications

References 45 publications

Differential Roles for Cytosolic and Microsomal Ca²⁺-Independent Phospholipase A₂in Cell Growth and Maintenance of Phospholipids

Differential Roles for Cytosolic and Microsomal Ca²⁺-Independent Phospholipase A₂in Cell Growth and Maintenance of Phospholipids

Src-dependent STAT-3-mediated Expression of Monocyte Chemoattractant Protein-1 Is Required for 15(S)-Hydroxyeicosatetraenoic Acid-induced Vascular Smooth Muscle Cell Migration

Arachidonic Acid Stimulates Cell Adhesion through a Novel p38 MAPK-RhoA Signaling Pathway That Involves Heat Shock Protein 27

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

Cited by 53 publications

References 45 publications

Differential Roles for Cytosolic and Microsomal Ca2+-Independent Phospholipase A2in Cell Growth and Maintenance of Phospholipids

Differential Roles for Cytosolic and Microsomal Ca2+-Independent Phospholipase A2in Cell Growth and Maintenance of Phospholipids

Src-dependent STAT-3-mediated Expression of Monocyte Chemoattractant Protein-1 Is Required for 15(S)-Hydroxyeicosatetraenoic Acid-induced Vascular Smooth Muscle Cell Migration

Arachidonic Acid Stimulates Cell Adhesion through a Novel p38 MAPK-RhoA Signaling Pathway That Involves Heat Shock Protein 27

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Differential Roles for Cytosolic and Microsomal Ca²⁺-Independent Phospholipase A₂in Cell Growth and Maintenance of Phospholipids

Differential Roles for Cytosolic and Microsomal Ca²⁺-Independent Phospholipase A₂in Cell Growth and Maintenance of Phospholipids