Targeting cyclooxygenase-2 in human neoplasia

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Targeting cyclooxygenase-2 in human neoplasia Andrew J Dannenberg, Kotha Subbaramaiah Cancer Cell Volume 4, Issue 6, Pages 431-436 (December 2003) DOI: 10.1016/S1535-6108(03)00310-6

Figure 1 Arachidonic acid metabolism Arachidonic acid, released from membrane phospholipids by phospholipase A2 (PLA2), is metabolized by cyclooxygenases to prostaglandin H2 (PGH2) in two steps. PGH2 is converted to a variety of prostanoids by specific isomerases. Cancer Cell 2003 4, 431-436DOI: (10.1016/S1535-6108(03)00310-6)

Figure 2 Regulation of COX-2 expression in cancers COX-2 is induced by a variety of stimuli, including oncogenes, growth factors, tumor promoters (phorbol esters, PMA), and chemotherapy (taxanes). Stimulation of PKC or Ras signaling enhances mitogen-activated protein kinase (MAPK) activity that results, in turn, in increased COX-2 transcription. A variety of transcription factors including AP-1 and NF-κB mediate the induction of COX-2. COX-2 can also be regulated by posttranscriptional mechanisms. The 3′-untranslated region (3′-UTR) of COX-2 mRNA contains a series of AU-enriched elements (ARE) that regulate message stability. Augmented binding of HuR, an RNA binding protein, to the AREs of the COX-2 3′-UTR is responsible, in part, for the observed increase in COX-2 message stability in some tumors. Cancer Cell 2003 4, 431-436DOI: (10.1016/S1535-6108(03)00310-6)

Figure 3 PGE2 activates cellular signal transduction pathways that have been implicated in carcinogenesis PGE2 activates cellular signaling in an EP receptor-dependent fashion. PGE2-mediated activation of EP2 and EP4 receptors leads to enhanced adenylate cyclase activity and cAMP production. cAMP stimulates expression of PKA-CREB-dependent genes including amphiregulin. Amphiregulin, a ligand of EGFR, activates EGFR-Ras-MAPK signaling. Additionally, activation of EP2 or EP4 enhances TCF-β-catenin-mediated transcription of genes including cyclin D1. Both the cAMP/PKA and phosphoinositide 3-kinase (PI3-K) pathways have been implicated in the activation of TCF-β-catenin-mediated transcription. Cancer Cell 2003 4, 431-436DOI: (10.1016/S1535-6108(03)00310-6)