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Novel Role of Thromboxane Receptors β Isoform in Bladder Cancer Pathogenesis

Departments of ¹ Pathology and Laboratory Medicine, ² Biostatistics, Bioinformatics and Epidemiology, ³ Pharmacology and Medicine, and ⁴ Biochemistry and Molecular Biology, and ⁵ Hollings Cancer Center, Medical University of South Carolina, Charleston, South Carolina; ⁶ Departments of Cardiothoracic Surgery and Pathology, Albert Einstein College of Medicine, Bronx, New York; and ⁷ Urology and Nephrology Center, Mansoura University, Mansoura, Egypt

Requests for reprints: Omar Moussa, Hollings Cancer Center, Room 313, Medical University of South Carolina, 86 Jonathan Lucas Street, Charleston, SC 29425. Phone: 843-792-1794; Fax: 843-792-5002; E-mail: moussa{at}musc.edu.

Key Words: bladder cancer • GPCR • thromboxane receptor

These studies were undertaken to determine the potential role of thromboxane receptors (TP) in bladder cancer. The data reported herein show that expression of the TP-β receptor protein is increased in tissue obtained from patients with bladder cancer and associated with a significantly poorer prognosis (P < 0.005). Bladder cancer cell lines express the TP-β isoform, unlike immortalized nontransformed urothelial cells (SV-HUC) that express only the TP- isoform. TP-β receptor expression, but not TP-, promoted cell proliferation, migration, and invasion in vitro, and also resulted in malignant transformation of SV-HUC cells in vivo. Agonist-mediated phosphorylation of extracellular signal-regulated kinase and FAK was dependent on the expression of TP-β. Furthermore, TP-β mediated multiple biological effects by signaling through either G-protein subunit 12 or β-arrestin 2. Treatment of mice with the TP receptor antagonist GR32191, alone or in combination with cisplatin, significantly delayed tumor onset and prolonged survival of mice transplanted with TCC-SUP bladder cancer cells compared with vehicle or cisplatin alone. These results support the model that the TP-β receptor isoform plays a unique role in bladder cancer progression and its expression may have predictive value and provide a novel therapeutic target. [Cancer Res 2008;68(11):4097–104]