Thromboxane A2 receptors in prostate carcinoma: expression and its role in regulating cell motility via small GTPase Rho.
Thromboxane A(2) (TxA(2)) is a prostanoid formed by thromboxane synthase using the cyclooxygenase product prostaglandin H(2) 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 TxA(2). Here, we report that human prostate cancer cells express functional receptors for TxA(2) (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 TxA(2). 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.
Nie
Daotai
D
Department of Medical Microbiology and Immunology, Southern Illinois University School of Medicine and SimmonsCooper Cancer Institute, Springfield, Illinois 62794, USA. dnie@siumed.edu
Guo
Yande
Y
Yang
Dianer
D
Tang
Yong
Y
Chen
Yakun
Y
Wang
Man-Tzu
MT
Zacharek
Alex
A
Qiao
Yan
Y
Che
Mingxin
M
Honn
Kenneth V
KV
D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid / Q000494:pharmacology; D000577:Amides / Q000494:pharmacology; D019086:Bridged Bicyclo Compounds, Heterocyclic; D002277:Carcinoma / Q000737:chemistry / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D002465:Cell Movement; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005231:Fatty Acids, Unsaturated; D006801:Humans; D006834:Hydrazines / Q000494:pharmacology; D008024:Ligands; D008297:Male; D011471:Prostatic Neoplasms / Q000737:chemistry / Q000378:metabolism / Q000473:pathology*; D011725:Pyridines / Q000494:pharmacology; D044244:Receptors, Thromboxane A2, Prostaglandin H2 / Q000032:analysis / Q000187:drug effects / Q000502:physiology*; D020742:rhoA GTP-Binding Protein / Q000032:analysis / Q000037:antagonists & inhibitors / Q000378:metabolism*
D000577:Amides; D019086:Bridged Bicyclo Compounds, Heterocyclic; D004791:Enzyme Inhibitors; D005231:Fatty Acids, Unsaturated; D006834:Hydrazines; D008024:Ligands; D011725:Pyridines; D044244:Receptors, Thromboxane A2, Prostaglandin H2; C108830:Y 27632; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; C045749:SQ 29548; D020742:rhoA GTP-Binding Protein