The role of prostacyclin synthase and thromboxane synthase signaling in the development and progression of cancer

Abstract

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 pro-tumor, an anti-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 over-expression has been shown to be chemopreventative 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 A C C E P T E D M A N U S C R I P T ACCEPTED MANUSCRIPTProstacyclin Synthase, Thromboxane Synthase and Cancer 4 growth and progression. Finally, we discuss current therapeutic strategies aimed at targeting these enzymes for the prevention/treatment of cancer. A C C E P T E D M A N U S C R I P T ACCEPTED MANUSCRIPTProstacyclin Synthase, Thromboxane Synthase and Cancer 5 IntroductionCancer causes seven million deaths annually, accounting for 12.5% of deaths worldwide. It is the second leading cause of death in the developed world and is among the three leading causes of death for adults in developed countries. It is estimated that, by 2020there will be 16 million new cases every year, representing a 50% increase in cancer incidence [1].The arachidonic acid pathway is responsible for the generation of a wide variety of bioactive metabolites. These metabolites, otherwise known as eicosanoids, have beenshown to be involved in many different pathologies, including inflammation and cancer [2].Arachidonic acid can be metabolised into the biologically active eicosanoids via the action of three separate groups of enzymes: cyclooxygenases (COX), lipoxygenases (LOX), and epoxygenases (cyctochrome P450). The COX enzymes catalyse the first step in the synthesis of prostanoids from arachidonic acid [3]. ...

4-Methylnitrosamino-1-3-pyridyl-1-butanone (NNK) promotes lung cancer cell survival by stimulating thromboxane A2 and its receptor

“…to an increase in apoptosis regardless of cell type, which is supported by the previous reports showing that inhibition of TxAS resulted in apoptosis in bladder (Moussa et al, 2008a) and lung (Cathcart et al, 2010) cancer cells, and that treatment with TxA 2 receptor antagonists also caused significant apoptosis in bladder cancer cells (Moussa et al, 2008b).…”

“…In addition, the bladder cancer cells transfected with b-isoform of TxA 2 receptor and stimulated with U46619 resulted in a significant increase in cellular growth rate and PCNA expression (Moussa et al, 2008b). A recent study has also reported that treatment of two NSCLC cell lines with another selective TxAS inhibitor ozagrel induced a significant reduction in cell proliferation (Cathcart et al, 2010). We have further demonstrated that the inhibitory effect of furegrelate or SQ29548 on NNK-promoted cell proliferation/survival is in part due Figure 5 Effects of blocking TxA 2 synthesis and action on Akt, ERK, JNK and p38 in cells exposed to NNK.…”

“…Therefore, TxAS and TxA 2 receptor have been selected to be the indicators of TxA 2 synthesis and action in ample studies. Overexpression of TxAS has been documented to have a potential role in promoting the progression of many types of cancers (Nie et al, 2004;Sakai et al, 2006;Moussa et al, 2008a;Leung et al, 2009;Cathcart et al, 2010). In addition to TxAS, the important role of TxA 2 receptor in tumorigenesis and cancer progression has emerged (Sakai et al, 2006;Wei et al, 2007;Li and Tai, 2009;Cathcart et al, 2010).…”

“…Overexpression of TxAS has been documented to have a potential role in promoting the progression of many types of cancers (Nie et al, 2004;Sakai et al, 2006;Moussa et al, 2008a;Leung et al, 2009;Cathcart et al, 2010). In addition to TxAS, the important role of TxA 2 receptor in tumorigenesis and cancer progression has emerged (Sakai et al, 2006;Wei et al, 2007;Li and Tai, 2009;Cathcart et al, 2010). Particularly, we have previously demonstrated that inhibition of TxAS results in the p27-related induction of cell death or apoptosis in both human non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC) cells (Leung et al, 2009), and other authors have recently reported that the activation of TxA 2 receptor induces cell proliferation in NSCLC cells (Li and Tai, 2009).…”

Microsomal prostaglandin E synthase-1 is involved in multiple steps of colon carcinogenesis

“…It has been known that PGD 2 and PGI 2 are anticarcinogenic agents (Keith et al, 2004;Park et al, 2007;Cathcart et al, 2010). PGD 2 is rapidly metabolized to 15-deoxy-D 12,14 -PGJ 2 , which inhibits tumor growth via a peroxisome proliferator-activated receptor g (PPARg)-dependent or -independent pathway (Scher and Pillinger, 2005;Mansure et al, 2009).…”