The role of prostacyclin synthase and thromboxane synthase signaling in the development and progression of cancer.
Prostacyclin synthase and thromboxane synthase signaling via arachidonic acid metabolism affects a number of tumor cell survival pathways such as cell proliferation, apoptosis, tumor cell invasion and metastasis, and angiogenesis. However, the effects of these respective synthases differ considerably with respect to the pathways described. While prostacyclin synthase is generally believed to be anti-tumor, a pro-carcinogenic role for thromboxane synthase has been demonstrated in a variety of cancers. The balance of oppositely-acting COX-derived prostanoids influences many processes throughout the body, such as blood pressure regulation, clotting, and inflammation. The PGI(2)/TXA(2) ratio is of particular interest in-vivo, with the corresponding synthases shown to be differentially regulated in a variety of disease states. Pharmacological inhibition of thromboxane synthase has been shown to significantly inhibit tumor cell growth, invasion, metastasis and angiogenesis in a range of experimental models. In direct contrast, prostacyclin synthase overexpression has been shown to be chemopreventive in a murine model of the disease, suggesting that the expression and activity of this enzyme may protect against tumor development. In this review, we discuss the aberrant expression and known functions of both prostacyclin synthase and thromboxane synthase in cancer. We discuss the effects of these enzymes on a range of tumor cell survival pathways, such as tumor cell proliferation, induction of apoptosis, invasion and metastasis, and tumor cell angiogenesis. As downstream signaling pathways of these enzymes have also been implicated in cancer states, we examine the role of downstream effectors of PGIS and TXS activity in tumor growth and progression. Finally, we discuss current therapeutic strategies aimed at targeting these enzymes for the prevention/treatment of cancer.
Cathcart
Mary-Clare
MC
Department of Surgery, Trinity Health Sciences Centre, St. James's Hospital, Dublin 8, Ireland. cathcarm@tcd.ie
Reynolds
John V
JV
O'Byrne
Kenneth J
KJ
Pidgeon
Graham P
GP
D000818:Animals; D003577:Cytochrome P-450 Enzyme System / Q000502:physiology*; D018450:Disease Progression; D006801:Humans; D019746:Intramolecular Oxidoreductases / Q000502:physiology*; D009369:Neoplasms / Q000201:enzymology / Q000503:physiopathology*; D015398:Signal Transduction; D013930:Thromboxane-A Synthase / Q000502:physiology*
D003577:Cytochrome P-450 Enzyme System; D019746:Intramolecular Oxidoreductases; C022461:prostacyclin synthetase; D013930:Thromboxane-A Synthase