The Role of Arachidonic Acid Regulatory Enzymes in Colorectal Disease

Abir, Farshad; Alva, Suraj; Kaminski, Donald L.; Longo, Walter E.

doi:10.1007/s10350-005-0015-y

Cited by 16 publications

(11 citation statements)

References 118 publications

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“…These alterations have provided the rationale for the use of non-steroidal anti-inflammatory drugs (NSAIDs) as chemoprevention agents against certain forms of cancer [6]. Despite their clinical effectiveness, however, NSAID treatment is often associated with adverse side effects, including gastrointestinal bleeding and cardiovascular toxicity [7]. Based on these adverse effects, other components of the AA cascade, including cPLA 2 α, have been considered as potential targets for therapy and chemoprevention.…”

Section: Overviewmentioning

confidence: 99%

Roles of cPLA2α and arachidonic acid in cancer

Nakanishi

Rosenberg

2006

Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biolog

102

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Phospholipase A 2 s (PLA 2 s) are key enzymes that catalyze the hydrolysis of membrane phospholipids to release bioactive lipids that play an important role in normal cellular homeostasis. Under certain circumstances, disrupted production of key lipid mediators may adversely impact physiological processes, leading to pathological conditions such as inflammation and cancer. In particular, cytosolic PLA 2 α (cPLA 2 α) has a high selectivity for liberating arachidonic acid (AA) that is subsequently metabolized by a panel of downstream enzymes for eicosanoid production. Although concentrations of free AA are maintained at low levels in resting cells, alterations in AA production, often resulting from dysregulation of cPLA 2 α activity, are observed in transformed cells. In this review, we summarize recent evidence that cPLA 2 α plays a role in the pathogenesis of many human cancers. Much of this evidence has been accumulated from functional studies using cPLA 2 α-deficient mice, as well as mechanistic studies in cell culture. We also discuss the potential contribution of cPLA 2 α and AA to apoptosis, and the regulatory mechanisms leading to aberrant expression of cPLA 2 α.

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Section: Overviewmentioning

confidence: 99%

Roles of cPLA2α and arachidonic acid in cancer

Nakanishi

Rosenberg

2006

Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biolog

102

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“…7,8 AA produced in cells by DAG-lipase and phospholipase A 2 (PLA 2 ) is further metabolized by lipoxygenase (Lox), cyclooxygenase (Cox) and cytochrome p450. 9 In addition to the direct activating effect of AA, eicosanoids derivatives, leukotrienes or 12(S)-HETE or 15(S)-HETE, produced by 5-, 12-, and 15-Lox, also activate NADPH oxidase to stimulate superoxide production. 8,10,11 To date, the involvement of AA metabolism in the regulation of Nox1 has not been addressed.…”

mentioning

confidence: 99%

Nox1 downstream of 12‐lipoxygenase controls cell proliferation but not cell spreading of colon cancer cells

Carvalho

Sadok

Bourgarel-Rey

et al. 2007

Intl Journal of Cancer

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The catalytic subunit of the NADPH oxidase complex, Nox1 (homologue of gp91phox/Nox2), expressed mainly in intestinal epithelial and vascular smooth muscle cells, functions in innate immune defense and cell proliferation. The molecular mechanisms underlying these functions, however, are not completely understood. We measured Nox1-dependent O 2 2 production during cell spreading on Collagen IV (Coll IV) in colon carcinoma cell lines. Knocking down Nox1 by shRNA, we showed that Nox1-dependent O 2 2 production is activated during cell spreading after 4 hr of adhesion on Collagen IV. Nox1 activation during cell spreading relies on Rac1 activation and arachidonic metabolism. Our results showed that manoalide (a secreted phospholipase A2 inhibitor) and cinnamyl-3,4-dihydroxy-a-cyanocinnamate (a 12-lipoxygenase inhibitor) inhibit O 2 2 production, cell spreading and cell proliferation in these colonic epithelial cells. 12-Lipoxygenase inhibition of ROS production and cell spreading can be reversed by adding 12-HETE, a 12-lipoxygenase product, supporting the specific effect observed with cinnamyl-3,4-dihydroxy-a-cyanocinnamate. In contrast, Nox1 shRNA and DPI (NADPH oxidase inhibitor) weakly affect cell spreading while inhibiting O 2 2 production and cell proliferation. These results suggest that the 12-lipoxygenase pathway is upstream of Nox1 activation and controls cell spreading and proliferation, while Nox1 specifically affects cell proliferation. ' 2007 Wiley-Liss, Inc.Key words: NADPH oxidase; Nox1; colon; integrins; arachidonic acidThe phagocytic NADPH oxidase is composed of 5 subunits, including p22phox and gp91 phox that constitute the membranebound flavocytochrome b 558 , and p40 phox , p47phox and p67 phox that translocate from the cytoplasm to the membrane upon cell activation.1 In addition, the small Rac GTPase have emerged as important functional components that are indispensable for NADPH oxidase activity. Since the initial identification of Nox1 (gp91 phox homolog) in human Caco-2 colon carcinoma cells, the biological significance of superoxide production by NAPDH oxidase in nonphagocytic cells has garnered much interest.2 In contrast to gp91phox/Nox2, which catalyzes a massive and explosive production of superoxide involved in host defense, Nox1 controls a lower superoxide production that acts as mediator of cell signaling. 2Nox1 is expressed mainly in normal and cancerous intestinal epithelial cells and vascular smooth muscle cells. Although being the subject of intense investigation, the role and the endogenous regulation of Nox1 in colon epithelial cells is still unclear.3,4 In colon carcinoma cells, homologs of p47 phox and p67 phox , respectively called Noxo1 (for Nox organizer 1) and Noxa1 (for Nox activator 1), have recently been identified. 5,6 In contrast to p47phox , Noxo1 appears to be constitutively associated with the NADPH oxidase complex.Activation of NADPH oxidase is dependent upon lipid mediators, such as phosphatidic and arachidonic acids and phosphatidylinositol. Arachidonic acid (AA)...

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“…The effects of n-6 PUFAs are primarily mediated by AA-derived eicosanoids. The anti-inflammatory and anticancer effects of NSAIDs, which function as specific inhibitors of AA metabolism, confirmed the significance of eicosanoids in cancer development [99, 100]. …”

Section: Dietary Factors and Colon Cancermentioning

confidence: 99%

Interaction of Dietary Fatty Acids with Tumour Necrosis Factor Family Cytokines during Colon Inflammation and Cancer

Hofmanová

Straková

Vaculová

et al. 2014

Mediators of Inflammation

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Intestinal homeostasis is precisely regulated by a number of endogenous regulatory molecules but significantly influenced by dietary compounds. Malfunction of this system may result in chronic inflammation and cancer. Dietary essential n-3 polyunsaturated fatty acids (PUFAs) and short-chain fatty acid butyrate produced from fibre display anti-inflammatory and anticancer activities. Both compounds were shown to modulate the production and activities of TNF family cytokines. Cytokines from the TNF family (TNF-α, TRAIL, and FasL) have potent inflammatory activities and can also regulate apoptosis, which plays an important role in cancer development. The results of our own research showed enhancement of apoptosis in colon cancer cells by a combination of either docosahexaenoic acid (DHA) or butyrate with TNF family cytokines, especially by promotion of the mitochondrial apoptotic pathway and modulation of NFκB activity. This review is focused mainly on the interaction of dietary PUFAs and butyrate with these cytokines during colon inflammation and cancer development. We summarised recent knowledge about the cellular and molecular mechanisms involved in such effects and outcomes for intestinal cell behaviour and pathologies. Finally, the possible application for the prevention and therapy of colon inflammation and cancer is also outlined.

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The Role of Arachidonic Acid Regulatory Enzymes in Colorectal Disease

Cited by 16 publications

References 118 publications

Roles of cPLA2α and arachidonic acid in cancer

Roles of cPLA2α and arachidonic acid in cancer

Nox1 downstream of 12‐lipoxygenase controls cell proliferation but not cell spreading of colon cancer cells

Interaction of Dietary Fatty Acids with Tumour Necrosis Factor Family Cytokines during Colon Inflammation and Cancer

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