Omega 3 but not omega 6 fatty acids inhibit AP-1 activity and cell transformation in JB6 cells

Liu, Guangming; Bibus, Doug; Bode, Ann M.; Ma, Weiya; Holman, Ralph T.; Dong, Zigang

doi:10.1073/pnas.131195198

Cited by 102 publications

(63 citation statements)

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“…In this regard, Liu et al, (2001) showed that in a mouse epidermal cell system, w3-PUFAs, but not the w6-arachidonic acid, effectively inhibited growth factor-triggered activator protein-1 transactivation. Moreover, w3-PUFAs down-regulated cytokine-triggered NF-kB activation and subsequent gene transcription in endothelial cells (McGuinness et al, 2008) as well as in macrophages (Lo et al, 1999).…”

Section: Figurementioning

confidence: 99%

The ω3‐polyunsaturated fatty acid derivatives AVX001 and AVX002 directly inhibit cytosolic phospholipase A₂ and suppress PGE₂ formation in mesangial cells

Huwiler

Feuerherm

Sakem

et al. 2012

British J Pharmacology

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BACKGROUND AND PURPOSEw3-polyunsaturated fatty acids (w3-PUFAs) are known to exert anti-inflammatory effects in various disease models although their direct targets are only poorly characterized. EXPERIMENTAL APPROACHHere we report on two new cPLA2 inhibitors, the w3-derivatives AVX001 and AVX002, and their effects on inflammatory PGE2 production in cultures of renal mesangial cells. KEY RESULTSAVX001 and AVX002 dose-dependently inhibited the group IVA cytosolic phospholipase A2 (cPLA2) in an in vitro activity assay with similar IC50 values for AVX001 and AVX002, whereas the known cPLA2 inhibitor AACOCF3 was less potent and docosahexaenoic acid (DHA) was inactive. In renal mesangial cells, AVX001 and AVX002 suppressed IL-1b-induced PGE2 synthesis. Mechanistically, this effect occurred by a down-regulation of IL-1b-induced group IIA-sPLA2 protein expression, mRNA expression and promoter activity. A similar but less potent effect was seen with AACOCF3 and no effect was seen with DHA. As gene expression of sPLA2 is known to be regulated by the transcription factor NF-kB, we further investigated NF-kB activation. Both compounds prevented NF-kB activation by blocking degradation of the inhibitor of kB. CONCLUSIONS AND IMPLICATIONSThese data show for the first time that the novel cPLA2 inhibitors AVX001 and AVX002 exert an anti-inflammatory effect in cultures of renal mesangial cells and reduce the pro-inflammatory mediator PGE2 through an inhibitory effect on NF-kB activation. Therefore, these compounds may represent promising novel drugs for the treatment of inflammatory disorders. AbbreviationsAACOCF3, ATK, arachidonyl-trifluoromethyl ketone; AVX001, 1-octadeca-2,6,9,12,15-pentaenylsulfanyl-propan-2-one; AVX002, 1-octadeca-3,6,9,12,15-pentaenylsulfanyl-propan-2-one; DHA, docosahexaenoic acid; EPA, eicosapentaenoic acid; IkB, inhibitor of kB; MAFP, methyl-arachidonyl fluorophosphonate; PAF-AH, PAF acetylhydrolase; PUFA, polyunsaturated fatty acid; RT-PCR, reverse transcriptase-PCR BJP British Journal of Pharmacology DOI:10.1111DOI:10. /j.1476DOI:10. -5381.2012 British Journal of Pharmacology (2012) IntroductionMesangial cells are specialized smooth muscle-like cells located in the renal glomerulus and are not only involved in the regulation of the glomerular filtration rate and in the preservation of the structural integrity of the glomerulus, but also play a central role in most pathological processes of the renal glomerulus (Kashgarian and Sterzel, 1992;Pfeilschifter, 1994;Gómez-Guerrero et al., 2005). Upon activation by a variety of pro-inflammatory cytokines, mesangial cells respond with three prominent reactions which are all hallmarks of many forms of glomerulonephritis: (i) increased proliferation; (ii) increased mediator production, including cytokines, chemokines, NO, superoxide radicals and PGs; and (iii) increased extracellular matrix production (Kashgarian and Sterzel, 1992;Pfeilschifter, 1994). The detailed mechanisms underlying these cellular responses are still not completely understood. One importan...

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Section: Figurementioning

confidence: 99%

The ω3‐polyunsaturated fatty acid derivatives AVX001 and AVX002 directly inhibit cytosolic phospholipase A₂ and suppress PGE₂ formation in mesangial cells

Huwiler

Feuerherm

Sakem

et al. 2012

British J Pharmacology

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“…Furthermore, asphalt fumes promote cell transformation. Up-regulation of AP-1 activity is frequently associated with cell transformation, and blockage of AP-1 activity has been shown to reverse the transformation of mouse epidermal cells (10,13,17,18,40). Many intracellular signaling pathways either directly or indirectly regulate AP-1 activation and cell transformation.…”

Section: Fig 4 Effect Of Asphalt Fumes On Pi3k Activity In Jb6 Pmentioning

confidence: 99%

Exposure to Asphalt Fumes Activates Activator Protein-1 through the Phosphatidylinositol 3-Kinase/Akt Signaling Pathway in Mouse Epidermal Cells

Wang

Luo

2003

Journal of Biological Chemistry

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Occupational exposure to asphalt fumes may pose a health risk. Experimental studies using animal and in vitro models indicate that condensates from asphalt fumes are genotoxic and can promote skin tumorigenesis. Enhanced activity of activator protein-1 (AP-1) is frequently associated with the promotion of skin tumorigenesis. The current study investigated the effect of exposure to asphalt fumes on AP-1 activation in mouse JB6 P ؉ epidermal cells and the skin of transgenic mice expressing the AP-1 luciferase reporter gene. Asphalt fumes were generated from a dynamic generation system that simulated road-paving conditions. Exposure to asphalt fumes significantly increased AP-1 activity in JB6 P ؉ cells as well as in cultured keratinocytes isolated from transgenic mice expressing AP-1 reporter. In addition, topical application of asphalt fumes by painting the tail skin of mice increased AP-1 activity by 14-fold. Exposure to asphalt fumes promoted basal as well as epidermal growth factor-stimulated anchorage-independent growth of JB6 P ؉ cells in soft agar. It activated phosphatidylinositol 3-kinase and induced phosphorylation of Akt at Ser-473/Thr-308, and concurrently activated downstream p70 S6 kinase as well as glycogen synthase kinase-3␤. Asphalt fumes transiently activated c-Jun NH 2 -terminal kinases without affecting extracellular signal-regulated kinases and p38 mitogen-activated protein kinases. Further study indicated that blockage of phosphatidylinositol 3-kinase activation eliminated asphalt fume-stimulated AP-1 activation and formation of anchorage-independent colonies in soft agar. This is the first report showing that exposure to asphalt fumes can activate AP-1 and intracellular signaling that may promote skin tumorigenesis, thus providing important evidence on the potential involvement of exposure to asphalt fumes in skin carcinogenesis.

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“…Transformation-Increased AP-1 activity leads to malignant transformation, and thus, the suppression of AP-1 activity is suggested to be involved in the mechanisms of action of many potential chemopreventive agents (25)(26)(27). We therefore investigated whether NS-398 or piroxicam could block malignant cell transformation.…”

Section: Ns-398 or Piroxicam Inhibits Tpa-induced Ap-1 Activity And Cellmentioning

confidence: 99%

NS-398 and Piroxicam Suppress UVB-induced Activator Protein 1 Activity by Mechanisms Independent of Cyclooxygenase-2

Bode

Zhang

et al. 2003

Journal of Biological Chemistry

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Cyclooxygenases (COX) are rate-limiting enzymes that catalyze the conversion of arachidonic acid to prostaglandins, which are involved in many physiological and pathophysiological responses. COX-2, one of two isoforms of COX, was recently found to play an important role in carcinogenesis in many cell and tissue types. COX-2 inhibitors, which belong to the family of nonsteroidal anti-inflammatory drugs, are believed to be effective in many biological activities such as tumor chemoprevention because of their inhibition of COX-2. However, in the present study we found that both piroxicam, a general COX inhibitor, and NS-398, a COX-2 selective inhibitor, effectively suppressed the activation of transcription factor activator protein 1 (AP-1) induced by ultraviolet B (UVB) or 12-O-tetradecanoylphorbol-13-acetate in mouse epidermal JB6 cells. These COX-2 inhibitors could also inhibit 12-O-tetradecanoylphorbol-13-acetate-induced cell transformation. UVB significantly increased AP-1 activity in Cox-2 ؊/؊ fibroblasts transfected with an AP-1 luciferase reporter gene, and this increase was blocked by NS-389 or piroxicam. In JB6, Cox-2 ؊/؊ , or wild-type Cox-2 ؉/؉ cells, both NS-398 and piroxicam inhibited UVB-induced phosphorylation of c-Jun NH 2 -terminal kinases, the kinases that activate the AP-1/c-Jun complex. Based on our results, we propose that the inhibition of AP-1 activity by COX-2 inhibitors NS-398 or piroxicam may occur by a mechanism that is independent of COX-2. Cyclooxygenases (COX)1 are rate-limiting enzymes that catalyze the conversion of arachidonic acid to prostaglandins, which are involved in many normal and pathophysiological responses (1-3). Of the two known COX enzymes, COX-1 is expressed in nearly all cells, whereas COX-2 is primarily considered an inducible immediate-early gene product (4). COX-2 is suggested to play an important role in tumorigenesis because of epidemiological evidence showing that various types of cancers and transformed cells tend to overexpress COX-2 constitutively (5-10). Moreover, the tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA), epidermal growth factor, and ultraviolet (UV) irradiation can induce COX-2 protein expression in many tissues including the epidermis of skin and also in epidermal keratinocytes (11).COX inhibitors are known to function through the inhibition of the COX enzymes. However, other potential mechanisms are still being considered (12). COX inhibitors were reported to protect neurons against hypoxia/reperfusion through mechanisms independent of COX (13). We and others have shown that nonsteroidal anti-inflammatory drugs can block mitogeninduced transcription activator protein 1 (AP-1) activity and transactivation (14). Considering the important role of AP-1 in tumoroigensis, the inhibition of AP-1 is likely to be one of the major mechanisms involved in nonsteroidal anti-inflammatory drugs chemopreventive effects.The aim of this study was to determine whether a COX-2 highly selective inhibitor, N-(2-cyclohexyloxy-4-nitrophenyl) methanesulfonami...

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Omega 3 but not omega 6 fatty acids inhibit AP-1 activity and cell transformation in JB6 cells

Cited by 102 publications

References 48 publications

The ω3‐polyunsaturated fatty acid derivatives AVX001 and AVX002 directly inhibit cytosolic phospholipase A₂ and suppress PGE₂ formation in mesangial cells

The ω3‐polyunsaturated fatty acid derivatives AVX001 and AVX002 directly inhibit cytosolic phospholipase A₂ and suppress PGE₂ formation in mesangial cells

Exposure to Asphalt Fumes Activates Activator Protein-1 through the Phosphatidylinositol 3-Kinase/Akt Signaling Pathway in Mouse Epidermal Cells

NS-398 and Piroxicam Suppress UVB-induced Activator Protein 1 Activity by Mechanisms Independent of Cyclooxygenase-2

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Omega 3 but not omega 6 fatty acids inhibit AP-1 activity and cell transformation in JB6 cells

Cited by 102 publications

References 48 publications

The ω3‐polyunsaturated fatty acid derivatives AVX001 and AVX002 directly inhibit cytosolic phospholipase A2 and suppress PGE2 formation in mesangial cells

The ω3‐polyunsaturated fatty acid derivatives AVX001 and AVX002 directly inhibit cytosolic phospholipase A2 and suppress PGE2 formation in mesangial cells

Exposure to Asphalt Fumes Activates Activator Protein-1 through the Phosphatidylinositol 3-Kinase/Akt Signaling Pathway in Mouse Epidermal Cells

NS-398 and Piroxicam Suppress UVB-induced Activator Protein 1 Activity by Mechanisms Independent of Cyclooxygenase-2

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The ω3‐polyunsaturated fatty acid derivatives AVX001 and AVX002 directly inhibit cytosolic phospholipase A₂ and suppress PGE₂ formation in mesangial cells

The ω3‐polyunsaturated fatty acid derivatives AVX001 and AVX002 directly inhibit cytosolic phospholipase A₂ and suppress PGE₂ formation in mesangial cells