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Thromboxane A₂ Receptors in Prostate Carcinoma: Expression and Its Role in Regulating Cell Motility via Small GTPase Rho

¹ Department of Medical Microbiology, Immunology, and Cell Biology, Southern Illinois University School of Medicine and SimmonsCooper Cancer Institute, Springfield, Illinois and ² Department of Pathology, Wayne State University School of Medicine and Karmanos Cancer Institute, Detroit, Michigan

Requests for reprints: Daotai Nie, Department of Medical Microbiology and Immunology, Southern Illinois University School of Medicine and the SimmonsCooper Cancer Institute, P. O. Box 19626, Springfield, IL 62794. Phone: 217-545-9702; Fax: 217-545-3227; E-mail: dnie{at}siumed.edu or Kenneth V. Honn, Department of Pathology, Wayne State University, 431 Chemistry Building, Detroit, MI 48202. Fax: 313-577-0798; E-mail: k.v.honn{at}wayne.edu.

Thromboxane A₂ (TxA₂) is a prostanoid formed by thromboxane synthase using the cyclooxygenase product prostaglandin H₂ as the substrate. Previously, increased expression of thromboxane synthase was found in prostate tumors, and tumor cell motility was attenuated by inhibitors of thromboxane synthase. This study was undertaken to elucidate how tumor motility is regulated by TxA₂. Here, we report that human prostate cancer cells express functional receptors for TxA₂ (TP). Ligand binding assay found that PC-3 cells binded to SQ29548, a high-affinity TP antagonist, in a saturable manner with K_d of 3.64 nmol/L and B_max of 120.4 fmol per million cells. Treatment of PC-3 cells by U46619, a TP agonist, induced PC-3 cell contraction, which was blocked by pretreatment with the TP antagonist SQ29548 or pinane TxA₂. The migration of prostate cancer cells was significantly inhibited either by sustained activation of TP or by blockade of TP activation, suggesting that TP activation must be tightly controlled during cell migration. Further studies found that small GTPase RhoA was activated by TP activation, and pretreatment of PC-3 cells with Y27632, a Rho kinase (ROCK) inhibitor, blocked U46619-induced cell contraction. A dominant-negative mutant of RhoA also blocked U46619-induced cell contraction. Taken together, the data suggest that TPs are expressed in prostate cancer and activation of TPs regulates prostate cancer cell motility and cytoskeleton reorganization through activation of Rho. [Cancer Res 2008;68(1):115–21]

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