Prostaglandin Endoperoxide H Synthases (Cyclooxygenases)-1 and −2

Smith, William L.; Garavito, R. Michael; DeWitt, David L.

doi:10.1074/jbc.271.52.33157

Cited by 1,736 publications

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“…Thus, in agreement with data from other reports (2,7,36,46), the activities of prostaglandin H synthases and lipoxygenases are likely to be essential for survival of luteal cells from midphase corpus luteum. During the catalytic cycle, these enzymes consume nitric oxide and hydroperoxide including peroxynitrite (6,54). These activities may be the rationale of our observations mentioned above.…”

Section: Discussionsupporting

confidence: 53%

N‐acetylcysteine impairs survival of luteal cells through mitochondrial dysfunction

Löhrke

Weitzel

et al. 2010

Cytometry Pt A

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N-acetylcysteine (NAC) is known as an antioxidant and used for mucus viscosity reduction. However, this drug prevents or induces cell death depending on the cell type. The response of steroidogenic luteal cells to NAC is unknown. Our data shows that NAC can behave as an antioxidant or prooxidant in dependency on the concentration and mitochondrial energization. NAC elevated the flowcytometric-measured portion of hypodiploid (dying) cells. This rise was completely abolished by aurintricarboxylic acid, an inhibitor of topoisomerase II. NAC increased the secretion of nitric oxide and cellular nitrotyrosine. An image analysis indicated that cells pretreated with NAC and loaded with DHR showed a fluorescent structure probably elicited by the oxidative product of DHR, rhodamine 123 that sequesters mitochondrially. Pretreating luteal cells with NAC or adding NAC directly to mitochondrial fractions followed by assessing the mitochondrial transmembrane potential difference (Dw) by the JC-1 technique demonstrated a marked decrease in Dw. A protonophore restored Dw and rotenone (an inhibitor of respiratory chain complex I) inhibited mitochondrial recovering. Thus, in steroidogenic luteal cells from healthy mature corpus luteum, NAC impairs cellular survival by interfering with mitochondrial metabolism. The protonophoreinduced recovering of NAC-provoked decrease in Dw indicates that an ATP synthasefavored route of H 1 re-entry to the matrix is essentially switched off by NAC while other respiratory chain complexes remain intact. These data may be important for therapeutic timing of treatments with NAC. ' 2010 International Society for Advancement of Cytometry Key terms luteal cells; antioxidant; redox imbalance; dihydrorhodamine 123; flow cytometry; mitochondrial dysfunction; viability THE corpus luteum is a transient ovarian steroidogenic gland, which develops within few days from the ovulated follicle to establish embryonic development. Intense vascularization is essential for maturation and maintenance of a healthy gland (1,2). The mature mid-luteal phase corpus luteum secretes large quantities of progesterone, a derivative from its mitochondrially formed precursor, pregnenolone.Steroidogenesis-dependent oxy-radicals and oxidants are generated during intramitochondrial conversion of cholesterol through the activity of NADPH-dependent cholesterol monooxygenase (side chain cleaving). It catalyzes in a phospholipid-assisted manner the formation of pregnenolone. This process is accompanied by an electron leakage into the mitochondrial matrix (3) and the synthesis of 4-methylpental as byproduct (4,5). In addition, regulatory constituents driving enhanced steroidogenesis are generated by the cyclooxygenase and lipoxygenase pathways which require reactive oxygen species. For instance, cyclooxygenase has an absolute requirement for hydroperoxide to catalyze oxygenation of lipids with a lipoperoxidation as the first step in forming prostanoids (6). In turn, high concentration of antioxidants and oxidant-detoxifying enzym...

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Section: Discussionsupporting

confidence: 53%

N‐acetylcysteine impairs survival of luteal cells through mitochondrial dysfunction

Löhrke

Weitzel

et al. 2010

Cytometry Pt A

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“…Cyclooxygenases (COX) are intracellular proteins that catalyse the rate-limiting step in the synthesis of prostaglandins (PGs), a potent group of autocrine and paracrine lipid mediators (Mitchell et al, 1995;Smith et al, 1996;Chen et al, 2000) that are implicated in many normal cellular and pathophysiological processes (Mitchell et al, 1995;Portanova et al, 1996;Smith et al, 1996;Chen et al, 2000). Two forms of COX have been identified to date: the constitutively expressed form COX-1, and the inducible form COX-2.…”

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confidence: 99%

Upregulation of cyclooxygenase-2 is accompanied by increased expression of nuclear factor-κB and IκB kinase-α in human colorectal cancer epithelial cells

et al. 2003

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Cyclooxygenase-2 (COX-2) is selectively overexpressed in colorectal tumours. The mechanism of COX-2 induction is not fully understood, but requires de novo messenger RNA and protein synthesis, indicating regulation at the transcriptional level. Sequence analysis of the 5 0 -flanking region of the COX-2 gene shows two nuclear factor-kB (NF-kB) sites. Inhibition of this protein in model cell culture systems attenuates COX-2 expression and implies that NF-kB plays an important role in COX-2 induction. We measured COX-2, NF-kB and IkB kinase a (IKKa) protein expression in matched colonic biopsy samples comprising both nontumour and adjacent tumour tissue from 32 colorectal cancer patients using immunohistochemistry. There was none or very little expression of COX-2, NF-kB and IKKa in non-neoplastic colon epithelial cells, while the expression of all three of these proteins was significantly increased (Po0.05, Wilcoxon's signed rank test) in adjacent cancerous cells. Moreover, all three proteins were found to be coexpressed in the neoplastic epithelium, with the expression of COX-2 and NF-kB highly correlated (Pearson's correlation, Po0.005). There was no apparent correlation between enhanced COX-2, NF-kB or IKKa expression and tumour Dukes' stages. Our results are compatible with the hypothesis that IKKa and NF-kB are involved in COX-2 induction in these tumours and the lack of association between COX-2 expression and severity of disease as measured by Dukes' stage is consistent with the proposal that COX-2 expression is an early postinitiation event.

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“…In addition, we demonstrated that HER2 and HER3 receptors in colorectal cancer cells are constitutively phosphorylated on tyrosine residues and form heterodimeric complexes in the absence of exogenous NDF. Inhibition of HER2/HER3 signaling by an anti-HER3 mAb against the ligand binding site resulted in a decrease in the levels of constitutively activated HER2/Introduction Accumulating evidence suggests that colorectal tumorigenesis may be regulated by the growth factorinducible form of cyclooxygenase-2 (COX-2), an enzyme responsible for the conversion of arachidonic acid to prostaglandins Smith et al, 1996). PGEs appear to play a variety of roles in the gastrointestinal tract, including participation in physiological secretion and motility, and also in pathologic processes such as neoplasia (Kutchera et al, 1996;Eberhart, 1994;DuBois et al, 1996).…”

mentioning

confidence: 99%

“…PGEs appear to play a variety of roles in the gastrointestinal tract, including participation in physiological secretion and motility, and also in pathologic processes such as neoplasia (Kutchera et al, 1996;Eberhart, 1994;DuBois et al, 1996). The primary PGEs generated in the colorectum appear to be PGE2 (Smith et al, 1996). Recent studies have shown the increased levels of COX-2 and PGE2 in colorectal adenocarcinomas compared to adjacent normal-appearing mucosa (Kutchera et al, 1996;Eberhart, 1994;DuBois, et al, 1996) and inhibition of COX-2 enzyme by speci®c COX-2 inhibitors reduces tumor formation, and regresses pre-existing tumors (Boolbol et al, 1996;Sheng et al, 1997;Chiu et al, 1997).…”

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confidence: 99%

Regulation of Cyclooxygenase-2 pathway by HER2 receptor

et al. 1999

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Emerging lines of evidence suggest that in addition to growth factors, the process of colorectal tumorigenesis may also be driven by the upregulation of the inducible form of cyclooxygenase-2 (COX-2), an enzyme responsible for the conversion of arachidonic acid to PGEs. The present study was undertaken to investigate the expression and activation of the HER family members, and to explore the regulation of COX-2 expression by the HER2 pathway in human colorectal cancer cells. Here, we report that human colorectal cancer cell lines express abundant levels of HER2 and HER3 receptors, and are growth-stimulated by recombinant neu-di erentiation factor-beta 1 (NDF). NDF-treatment of colorectal cancer cells was accompanied by increased tyrosine phosphorylation and heterodimerization of HER3 with HER2. In addition, we demonstrated that HER2 and HER3 receptors in colorectal cancer cells are constitutively phosphorylated on tyrosine residues and form heterodimeric complexes in the absence of exogenous NDF. Inhibition of HER2/HER3 signaling by an anti-HER3 mAb against the ligand binding site resulted in a decrease in the levels of constitutively activated HER2/ HER3 heterodimers, and the unexpected reduction of COX-2 expression. Activation of the HER2/HER3 pathway by NDF induced the activation of COX-2 promoter, expression of COX-2 mRNA, COX-2 protein and accumulation of prostaglandin E2 in the culture medium. Finally, we demonstrated that NDF promotes the ability of colorectal cancer cells to survive in an extracellular matrix milieu, such as Matrigel, and also to invade through a 8 mm porous membrane. These biological activities of NDF and its stimulation of cell proliferation are blocked by a speci®c inhibitor of COX-2. Taken together, our ®ndings provide the ®rst biochemical evidence of a possible role of the COX-2 pathway in the mitogenic action of NDF in colorectal cancer cells where it may be constitutively upregulated due to the autocrine/paracrine activation of HER2/ HER3 heterodimers.

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Prostaglandin Endoperoxide H Synthases (Cyclooxygenases)-1 and −2

Cited by 1,736 publications

References 68 publications

N‐acetylcysteine impairs survival of luteal cells through mitochondrial dysfunction

N‐acetylcysteine impairs survival of luteal cells through mitochondrial dysfunction

Upregulation of cyclooxygenase-2 is accompanied by increased expression of nuclear factor-κB and IκB kinase-α in human colorectal cancer epithelial cells

Regulation of Cyclooxygenase-2 pathway by HER2 receptor

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