Prognostic and Functional Significance of Thromboxane Synthase Gene Overexpression in Invasive Bladder Cancer

Abstract

Thromboxane synthase (TXAS) is one of the enzymes downstream from cyclooxygenase-2 and catalyzes the synthesis of thromboxane A 2 (TXA 2 ). TXAS was among the genes we identified based on its overexpression in invasive bladder tumors. TXAS is overexpressed in common forms of bladder tumors: 69 of 97 (71.1%) transitional cell carcinoma (TCC), 38 of 53 (71.6%) squamous cell carcinoma, and 5 of 11 (45.5%) adenocarcinoma relative to nontumor tissue. Overall, 112 of 161 (69.5%) invasive tumors exhibited elevated expression. Significantly, patients with tumors having >4-fold levels of TXAS expression showed significant statistical evidence of lower overall survival expressed by the estimated hazard ratio of 2.74 with P = 0.009 in Cox's regression analysis. TXAS mRNA expression was found to be an independent prognostic marker for patients with bladder cancer. Treatment of bladder cancer cell lines (T24 and TCC-SUP) with TXAS inhibitors and TXA 2 (TP) receptor antagonists reduced cell growth, migration, and invasion, whereas TP agonists stimulated cell migration and invasion. The positive correlation between elevated TXAS expression and shorter patient survival supports a potential role for TXAS-regulated pathways in tumor invasion and metastases and suggests that modulation of the TXAS pathway may offer a novel therapeutic approach. (Cancer Res 2005; 65(24): 11581-7)

Inhibition of thromboxane synthase activity modulates bladder cancer cell responses to chemotherapeutic agents

“…The data are representative of seven cases that showed the same pattern of expression. Increased expression of TXAS protein with tumor grade is consistent with that observed with mRNA analyses (Moussa et al, 2005).…”

“…During molecular profiling of bladder cancer, we found that TXAS is overexpressed in both squamous cell carcinoma and transitional cell carcinoma (TCC) of the bladder (Moussa et al, 2005). Significantly, increased TXAS expression in patients with bladder cancer is negatively correlated with survival (Moussa et al, 2005). TXAS-specific inhibitors have been shown to suppress growth and reduce the migration and invasion of bladder cancer cells (Moussa et al, 2005).…”

“…Significantly, increased TXAS expression in patients with bladder cancer is negatively correlated with survival (Moussa et al, 2005). TXAS-specific inhibitors have been shown to suppress growth and reduce the migration and invasion of bladder cancer cells (Moussa et al, 2005). Several additional studies have shown a potential role of TXAS in promoting tumor invasion and metastases (Pradono et al, 2002;Kim et al, 2003;Nie et al, 2004;Watkins et al, 2005;Sakai et al, 2006).…”

Activation of thromboxane receptor α induces expression of cyclooxygenase-2 through multiple signaling pathways in A549 human lung adenocarcinoma cells

“…Induction of COX-2 expression by a TP agonist would naturally lead to increased PGE 2 and TXB 2 synthesis although we are not sure if the coupling enzymes, PGE synthase and thromboxane synthase, are also induced. However, both microsomal PGE synthase and thromboxane synthase are known to over-express in tumors [29,30], whereas the key PG catabolic enzyme, 15-hydroxyprostaglandin dehydrogenase, is demonstrated to underexpress in tumors [31]. In fact, the expressions of COX-2 and 15-hydroxyprostaglandin dehydrogenase were shown to be regulated reciprocally [32].…”

Alternative splicing of G protein-coupled receptors: physiology and pathophysiology

“…Thromboxane synthesis has been reported to be elevated in bladder cancers and inhibition of the synthesis or action of these prostanoid mediators can decrease rates of cell proliferation and migration [122]. In the late 1990s it was demonstrated that two isoforms of the thromboxane receptor (TP-α and TP-β), alternatively spliced at the C-terminus, have distinct agonist-induced internalization properties and abilities to bind β-arrestins [80], with only the TP-β isoform able to internalize in a ligand-dependent manner.…”