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(American Journal of Pathology. 2004;164:429-439.)
© 2004 American Society for Investigative Pathology

Differential Expression of Thromboxane Synthase in Prostate Carcinoma

Role in Tumor Cell Motility

Daotai Nie*, Mingxin Che{dagger}, Alex Zacharek*, Yan Qiao*, Li Li*, Xinglin Li{dagger}, Mario Lamberti*, Keqin Tang*, Yilong Cai*, Yande Guo*, David Grignon{dagger} and Kenneth V. Honn*{dagger}

From the Departments of Radiation Oncology* and Pathology,{dagger} Wayne State University School of Medicine and Karmanos Cancer Institute, Detroit, Michigan

Arachidonic acid metabolism through cyclooxygenase, lipoxygenase, or P-450 epoxygenase pathways can generate a variety of eicosanoids. Thromboxane synthase (TxS) metabolizes the cyclooxygenase product, prostanglandin H2, into thromboxane A2 (TXA2), which can cause vessel constriction, platelet activation, and aggregation. Here we demonstrate that human prostate cancer (PCa) cells express enzymatically active TxS and that this enzyme is involved in cell motility. In human PCa cell lines, PC-3, PC-3M, and ML-2 cells expressed higher levels of TxS than normal prostate epithelial cells or other established PCa cell lines such as DU145, LNCaP, or PPC-1. We cloned and sequenced the full-length TxS cDNA from PC-3 cells and found two changes in the amino acid residues. Immunohistochemical analysis of tumor specimens revealed that expression of TxS is weak or absent in normal differentiated luminal, or secretory cells, significantly elevated in less differentiated or advanced prostate tumors, and markedly increased in tumors with perineural invasion. TxS expressed in PC-3 cells was enzymatically active and susceptible to carboxyheptal imidazole, an inhibitor of TxS. The biosynthesis of TXA2 in PC-3 cells was dependent on COX-2, and to a lesser extent, COX-1. Treatment of PC-3 cells with a COX-1 selective inhibitor, piroxicam, reduced TXA2 synthesis by approximately 40%, while the COX-2 specific inhibitor NS398 reduced TXA2 production by ~80%. Inhibition of TxS activity or blockade of TXA2 function reduced PC-3 cell migration on fibronectin, while having minimal effects on cell cycle progression or survival. Finally, increased expression of TxS in DU145 cells increased cell motility. Our data suggest that human PCa cells express TxS and that this enzyme may contribute to PCa progression through modulating cell motility.




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