Prostaglandin E2 production in ovarian cancer cell lines is regulated by cyclooxygenase-1, not cyclooxygenase-2

Kino, Yuko; Kojima, Fumio; Kiguchi, Kazushige; Igarashi, Rie; Ishizuka, Bunpei; Kawai, Shinichi

doi:10.1016/j.plefa.2005.04.014

Cited by 35 publications

(35 citation statements)

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“…COX enzymes are required for ovarian function and many female reproductive processes, but overexpression of COX is associated with significant pathology. Increased expression of COX-2 is associated with manyepithelial carcinomas; however, COX-1 but not COX-2 overexpression has been shown to be associated with ovarian cancer [8,[21][22][23][24][25][26]. The laying hen provides an excellent model for studying normal ovarian functions, in particular ovulation [27,28].…”

Section: Discussionmentioning

confidence: 99%

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Cyclooxygenases expression and distribution in the normal ovary and their role in ovarian cancer in the domestic hen (Gallus domesticus)

Hales

Zhuge

Lagman

et al. 2008

Endocr

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Cyclooxygenase (COX) (PTGS) is the rate-limiting enzyme in the biosynthesis of prostaglandins. Two COX isoforms have been identified, COX-1 and COX-2, which show distinct cell-specific expression and regulation. Ovarian cancer is the most lethal gynecological malignancy and the © Humana Press Inc. 2008 Correspondence to: Dale Buchanan Hales, dbhale@uic.edu. HHS Public Access Author ManuscriptAuthor Manuscript Author ManuscriptAuthor Manuscript disease is poorly understood due to the lack of suitable animal models. The laying hen spontaneously develops epithelial ovarian cancer with few or no symptoms until the cancer has progresses to a late stage, similar to the human disease. The purpose of this study was to examine the relative expression and distribution of COX-1 and COX-2 in the ovaries of normal hens and in hens with ovarian cancer. The results demonstrate that COX-1 was localized to the granulosa cell layer and cortical interstitium, ovarian surface epithelium (OSE) and postovulatory follicle (POF) of the normal ovary. In ovarian cancer, COX-1 mRNA was significantly increased and COX-1 protein was broadly distributed throughout the tumor stroma. COX-2 protein was localized to the granulosa cell layer in the follicle and the ovarian stroma. COX-2 mRNA expression did not change as a function of age or in ovarian cancer. There was significantly higher expression of COX-1 mRNA in the first POF (POF-1) compared to POF-2 and POF-3. COX-2 mRNA expression was not significantly different among POFs. There was no difference in COX-1 or COX-2 mRNA in the OSE isolated from individual follicles in the follicular hierarchy. The results confirm previous findings of the high expression of COX-1 in ovarian tumors further supporting the laying hen as a model for ovarian cancer, and demonstrate for the first time the high expression of COX-1 in POF-1 which is the source of prostaglandins needed for oviposition.

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Section: Discussionmentioning

confidence: 99%

“…In contrast to most malignancies, however, COX-2 expression is downregulated in ovarian cancer [20]. Instead, COX-1 expression has been shown to be elevated in ovarian cancer [8,[21][22][23][24][25][26]. Whereas considerable research has focused on the role of COX-2 in ovulation and normal ovarian function, much less is known about COX-1.…”

Section: Introductionmentioning

confidence: 99%

Cyclooxygenases expression and distribution in the normal ovary and their role in ovarian cancer in the domestic hen (Gallus domesticus)

Hales

Zhuge

Lagman

et al. 2008

Endocr

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“…Significance of mPGES-1 Inhibition-PGE 2 is a key proinflammatory mediator of inflammation associated with various disease states, and increased PGE 2 requires both COX-2 and mPGES-1 (4,5,18,19,(35)(36)(37)(38). Nonselective and COX-2-selective NSAIDs reduce PGE 2 production by inhibiting COX-2 activity and are extensively used for reducing inflammation, pain, and fever (39).…”

Section: Discussionmentioning

confidence: 99%

Microsomal Prostaglandin E Synthase-1 Deficiency Is Associated with Elevated Peroxisome Proliferator-activated Receptor γ

Kapoor

Kojima

Qian

et al. 2007

Journal of Biological Chemistry

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mPGES-1 (microsomal PGE synthase-1) is an inducible enzyme that acts downstream of cyclooxygenase (COX) and specifically catalyzes the conversion of prostaglandin (PG) H 2 to PGE 2 under basal as well as inflammatory conditions. In this study, using mouse embryo fibroblasts (MEFs) isolated from mice genetically deficient for the mPges-1 gene, we show basal elevation of peroxisome proliferator-activated receptor ␥ (PPAR␥) expression (protein and mRNA) and transcriptional activity associated with reduced basal PGE 2 . We further show that basal mPGES-1-derived PGE 2 suppresses the expression of PPAR␥ through a cAMP-independent pathway involving phosphatidylinositol 3-kinase and Akt signaling. Using specific PPAR␥ agonist (rosiglitazone), PPAR␥ ligand (15-deoxy-⌬12,14-PGJ 2 ), and PPAR␥ inhibitor (GW9662), we confirm that activation of PPAR␥ blocks interleukin-1␤-induced up-regulation of COX-2, mPGES-1, and their derived PGE 2 . Furthermore, we demonstrate that up-regulation of PPAR␥ upon genetic deletion of mPGES-1 is responsible for reduced COX-2 expression under basal as well as interleukin-1␤-stimulated conditions. This study provides evidence for the first time that mPGES-1 deletion not only decreases proinflammatory PGE 2 but also up-regulates anti-inflammatory PPAR␥, which has the ability to suppress COX-2 and mPGES-1 expression and PGE 2 production. Thus, mPGES-1 inhibition may limit inflammation by multiple mechanisms and is a potential therapeutic target. Prostaglandins (PGs)2 are formed by metabolism of arachidonic acid by cyclooxygenases (COX) to generate an intermediate substrate, PGH 2 , which is further metabolized by terminal synthases to generate specific PGs (1, 2). mPGES-1, originally known as microsomal glutathione S-transferase 1-like 1 (MGST1-L1), is an inducible enzyme that acts downstream of COX and specifically catalyzes the conversion of PGH 2 to PGE 2 (3), most prominently in inflammatory conditions (4, 5). However, we have recently shown that mPGES-1 is critical for PGE 2 production under basal as well as inflammatory conditions (6).mPGES-1 is coordinately induced with COX-2 by inflammatory stimuli in a variety of cells and tissues (4, 7). PGE 2 is the most abundant PG associated with inflammatory conditions, and overproduction of PGE 2 coincides with increased COX-2 and mPGES-1 expression (4, 7). PGE 2 exerts the majority of its actions through a family of G protein-coupled receptors, including EP1, EP2, EP3, and EP4 (8). The effects of PGE 2 via these receptors are mediated through various downstream signaling pathways, including cAMP-dependent protein kinase, mitogen-activated protein kinase (MAP kinase), phosphatidylinositol 3-kinase (PI 3-kinase), and Akt (8 -10).Inhibition of PGE 2 production and action is associated with reduction of the pain and inflammation associated with a wide variety of diseases. Nonselective and COX-2-selective nonsteroidal anti-inflammatory drugs (NSAIDs) block PGE 2 production by inhibiting the activity of COX and are extensively used to treat arthritis a...

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“…Although some groups have reported high levels of COX-2 in ovarian cancer (Klimp et al, 2001;Matsumoto et al, 2001), others have reported elevated COX-1, but not COX-2, in ovarian cancer tissue samples (Dore et al, 1998;Gupta et al, 2003) or cell lines (Kino et al, 2005;Yang et al, 2005), suggesting tissue-specific roles for each isoform. Furthermore, Cox-1 over expression was previously demonstrated in tumors arising from p53-null mouse OSE cells also over expressing either c-myc and K-ras or c-myc and Akt (Daikoku et al, 2005), while Cox-2 was either not expressed or expressed at very low levels.…”

Section: Rational Drug Designmentioning

confidence: 99%

Role of p53 and Rb in Ovarian Cancer

Corney

Flesken‐Nikitin

Choi

et al.

Advances in Experimental Medicine and Biology

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Ovarian cancer remains a major health concern worldwide, primarily in postmenopausal women. Among the most common genetic alterations in human sporadic epithelial ovarian cancer (EOC) are p53 mutations, defective retinoblastoma (RB) pathway (p16 INK4a /RB) and activation of oncogenes such as c-myc, K-ras and Akt. Although these alterations are frequently associated with poor clinical prognosis, their specific contributions to EOC formation remain unclear. In order to gain a better understanding of the roles of these proteins in vivo, a number of mouse models have been generated, largely based upon inducing specific genetic lesions in the ovarian surface epithelium from which the majority of carcinomas are thought to arise in humans. Here, we review the role of tumor suppressor p53 and the Rb pathway in EOC with particular attention to association of p53 to high grade serous carcinomas as opposed to low grade and benign tumors. We also provide an overview of the utility and application of genetically engineered mouse models, in particular towards rational drug design and development of improved imaging techniques in ovarian cancer.

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Prostaglandin E2 production in ovarian cancer cell lines is regulated by cyclooxygenase-1, not cyclooxygenase-2

Cited by 35 publications

References 36 publications

Cyclooxygenases expression and distribution in the normal ovary and their role in ovarian cancer in the domestic hen (Gallus domesticus)

Cyclooxygenases expression and distribution in the normal ovary and their role in ovarian cancer in the domestic hen (Gallus domesticus)

Microsomal Prostaglandin E Synthase-1 Deficiency Is Associated with Elevated Peroxisome Proliferator-activated Receptor γ

Role of p53 and Rb in Ovarian Cancer

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