Document Detail


Differential expression of thromboxane synthase in prostate carcinoma: role in tumor cell motility.
MedLine Citation:
PMID:  14742249     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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 H(2), into thromboxane A(2) (TXA(2)), 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 TXA(2) 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 TXA(2) synthesis by approximately 40%, while the COX-2 specific inhibitor NS398 reduced TXA(2) production by approximately 80%. Inhibition of TxS activity or blockade of TXA(2) 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.
Authors:
Daotai Nie; Mingxin Che; Alex Zacharek; Yan Qiao; Li Li; Xinglin Li; Mario Lamberti; Keqin Tang; Yilong Cai; Yande Guo; David Grignon; Kenneth V Honn
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Publication Detail:
Type:  Comparative Study; Journal Article; Research Support, U.S. Gov't, Non-P.H.S.; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  The American journal of pathology     Volume:  164     ISSN:  0002-9440     ISO Abbreviation:  Am. J. Pathol.     Publication Date:  2004 Feb 
Date Detail:
Created Date:  2004-01-26     Completed Date:  2004-03-11     Revised Date:  2013-06-09    
Medline Journal Info:
Nlm Unique ID:  0370502     Medline TA:  Am J Pathol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  429-39     Citation Subset:  AIM; IM    
Affiliation:
Department of Radiation Oncology, Wayne State University School of Medicine and Karmanos Cancer Institute, Detroit, Michigan 48202, USA.
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MeSH Terms
Descriptor/Qualifier:
Amino Acid Sequence
Base Sequence
Blotting, Northern
Cell Line, Tumor
Cell Movement / drug effects,  physiology*
Cyclooxygenase 1
Cyclooxygenase 2
DNA, Complementary / analysis
Enzyme Inhibitors / pharmacology
Humans
Immunohistochemistry
Isoenzymes / metabolism
Male
Membrane Proteins
Molecular Sequence Data
Neoplasm Invasiveness
Prostaglandin-Endoperoxide Synthases / metabolism
Prostatic Neoplasms / enzymology*
Reverse Transcriptase Polymerase Chain Reaction
Thromboxane-A Synthase / biosynthesis*,  drug effects,  genetics
Grant Support
ID/Acronym/Agency:
CA-29997/CA/NCI NIH HHS
Chemical
Reg. No./Substance:
0/DNA, Complementary; 0/Enzyme Inhibitors; 0/Isoenzymes; 0/Membrane Proteins; EC 1.14.99.1/Cyclooxygenase 1; EC 1.14.99.1/Cyclooxygenase 2; EC 1.14.99.1/PTGS1 protein, human; EC 1.14.99.1/PTGS2 protein, human; EC 1.14.99.1/Prostaglandin-Endoperoxide Synthases; EC 5.3.99.5/Thromboxane-A Synthase
Comments/Corrections

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