Cyclooxygenase-2
(COX-2)

Prostaglandin G/H synthase-2 (PGHS-2)
Prostaglandin H synthase (PHS-2)
Prostaglandin endoperoxide synthase-2 (PTGS2)

Gene: maps to 1q25.2-q25.3; the single copy gene is 8.3 kb in size and consists in 10 exons and 9 introns. The largest exon encodes the entire 3'-UTR, containing 22 copies of the 'AUUUA' RNA instability element. Sequence analysis of the 5'-flanking region has shown several potential transcription regulatory sequences, including a TATA box, a C/EBP motif, two AP-2 sites, three SP1 sites, two NF-kappa B sites, a CRE motif and an Ets-1 site (Appleby S.B. et al., 1994).
mRNA: size: 4.4 kb.
Protein: inducible by mitogens, lipopolysaccharide (LPS), and phorbol myristate acetate (PMA). Induction by PMA is partially inhibited by pretreatment with dexamethasone. COX-2 is expressed in cells involved in inflammatory processes and is probably a key mediator in inflammation. It has been shown that COX-2 can modulate production of angiogenic factors by colon cancer cells. Moreover, in an in vitro model involving coculture of endothelial cells with colon carcinoma cells (CCC), CCC overexpressing COX-2 produced prostaglandins, proangiogenic factors, and stimulated both endothelial migration and tube formation, while control cells had little activity; the effect was inhibited by antibodies to combinations of angiogenic factors, by NS-398 (a selective COX-2 inhibitor), and by aspirin (Tsujii M. et al., 1998).

Cell lines:
- COX-2 was barely detectable but transiently induced by TPA in MCF-7 breast cancer cells (BCC); COX-2 was highly expressed in the invasive, metastatic MDA-MB-231 BCC (Liu X.-H. and Rose D.P., 1996).
- In a study involving 4 ER-negative human BCC lines, the MCF10A breast epithelial cell line, and the same non-cancerous line transfected with a mutated ras gene, the highly invasive MDA-MB-231 and Hs578T BCC lines, which possess a mutated Ki-ras and H-ras, respectively, expressed constitutive and inducible COX-2, and produced high prostaglandin E₂ (PGE₂) levels; in contrast, the less invasive MDA-MB-435 and SK-BR-3 BCC lines, without a mutated ras, possessed only low levels of COX-2, and secreted correspondingly low PGE₂ levels. Similarly, the ras transfectant, but not parental MCF10A cells, expressed inducible COX-2 (Gilhooly E.M. and Rose D.P., 1999).
- In MDA-MB-231 and Hs578T BCC, the COX-2 inhibitor, aspirin metabolite, salicylate inhibited PGE₂, interleukin-6, and interleukin-11 production and reduced cell proliferation (Sotiriou C. et al., 1999).

- Wnt-1 expression in the mouse mammary epithelial cell lines RAC311 and C57MG induces stabilization of cytosolic beta-catenin and morphological transformation. Expression of Wnt-1 in these cells caused transcriptional up-regulation of the cyclooxygenase-2 gene, resulting in increased levels of cyclooxygenase-2 mRNA and protein. Prostaglandin E2 production was increased as a consequence of the elevated cyclooxygenase-2 activity and could be decreased by treatment with a selective cyclooxygenase-2 inhibitor. Cyclooxygenase-2 thus appears to be a common downstream target for APC mutation and Wnt-1 expression (Howe L.R. et al., 1999).

Tumors:
- COX-2 was found by RT-PCR in 13/13 breast tumors (Parrett M.L. et al., 1997).
- COX-2 expression was found at mRNA (RNAse protection) and protein (immunohistochemistry) levels in 2/44 breast tumors (Hwang D. et al., 1998).

Appleby S.B. et al. (1994) Structure of the human cyclo-oxygenase-2 gene. Biochem. J. 302, 723-727.
Gilhooly E.M. and Rose D.P. (1999) The association between a mutated ras gene and cyclooxygenase-2 expression in human breast cancer cell lines. Int. J. Oncol. 15, 267-270.
Herschman H.R. (1994) Regulation of prostaglandin synthase-1 and prostaglandin synthase-2. (Review) Cancer Metastasis Rev. 13, 241-256.
Hla T. and Neilson K. (1992) Human cyclooxygenase-2 cDNA. Proc. Natl. Acad. Sci. USA 89, 7384-7388.
Howe L.R. et al. (1999) Transcriptional activation of cyclooxygenase-2 in Wnt-1-transformed mouse mammary epithelial cells. Cancer Res. 59, 1572-1577.
Hwang D. et al. (1998) Expression of cyclooxygenase-1 and cyclooxygenase-2 in human breast cancer. J. Natl. Cancer Inst. 90, 455-460.
Jones D.A. et al. (1993) Molecular cloning of human prostaglandin endoperoxidase synthase type II and demonstration of expression in response to cytokines. J. Biol. Chem. 12, 9049-9054.
Kosaka T. et al. (1994) Characterization of the human gene (PTGS2) encoding prostaglandin-endoperoxidase synthase 2. Eur. J. Biochem. 221, 889-897.
Kutchera W. et al. (1996) Prostaglandin H synthase 2 is expressed abnormally in human colon cancer: evidence for a transcriptional effect. Proc. Natl. Acad. Sci. USA 93, 4816-4820.
Liu X.-H. and Rose D.P. (1996) Differential expression and regulation of cyclooxygenase-1 and -2 in two human breast cancer cell lines. Cancer Res. 56, 5125-5127.
Parrett M.L. et al. (1997) Cyclooxygenase-2 gene expression in human breast cancer. Int. J. Oncol. 10, 503-508.
Sotiriou C. et al. (1999) The aspirin metabolite salicylate inhibits breast cancer cells growth and their synthesis of the osteolytic cytokines interleukins-6 and -11. Anticancer Res. 19, 2997-3006 (see abstract).
Tazawa R. et al. (1994) Characterization of the genomic structure, chromosomal location and promoter of human prostaglandin H synthase-2 gene. Biochem. Biophys. Res. Commun. 203, 190-199.
Tsujii M. et al. (1998) Cyclooxygenase regulates angiogenesis induced by colon cancer cells. Cell 93, 705-716.