Nitric oxide stimulates migration of human endothelial and prostate cancer cells through up-regulation of pleiotrophin expression and its receptor protein tyrosine phosphatase beta/zeta.
Pleiotrophin (PTN) is a secreted growth factor involved in angiogenesis and tumor growth. We have recently shown that low concentrations of hydrogen peroxide (HP) stimulate PTN expression, through activation of the transcription factor AP-1. In the present work, we studied the possible involvement of endothelial nitric oxide synthase (eNOS) and the role of nitric oxide (NO) in the regulation of PTN expression, as well as involvement of the latter in the NO-induced human endothelial and prostate cancer cell migration. Inhibition of eNOS or the downstream effector soluble guanylate cyclase (sGC) completely suppressed HP-induced AP-1 activities that lead to PTN expression and cell migration. The NO donor sodium nitroprusside (SNP) through activation of sGC significantly and concentration-dependently increased expression of PTN, through transcriptional activation of the corresponding gene. Moreover, SNP had no effect on the migration of stably transfected prostate cancer cells that do not express PTN and knockdown of PTN receptor protein tyrosine phosphatase beta/zeta (RPTPbeta/zeta) completely abolished SNP-induced cell migration. NO added exogenously or produced endogenously by low concentrations of HP through stimulation of sGC activates extracellular signal-regulated kinase[1/2] (ERK[1/2]) and leads to PTN expression and cell migration. On the other hand, p38, which also intervenes in the up-regulation of PTN expression by low concentrations of HP, seems to act upstream of eNOS and does not intervene in the SNP-induced PTN expression and cell migration. The above data suggest that PTN through its receptor RPTPbeta/zeta is a mediator of the stimulatory effects of eNOS/NO on human endothelial and prostate cancer cell migration.
Polytarchou
Christos
C
Laboratory of Molecular Pharmacology, Department of Pharmacy, University of Patras, Patras, Greece.
Hatziapostolou
Maria
M
Poimenidi
Evangelia
E
Mikelis
Constantinos
C
Papadopoulou
Ariadni
A
Parthymou
Anastasia
A
Papadimitriou
Evangelia
E
D002352:Carrier Proteins / Q000096:biosynthesis*; D002460:Cell Line; D045744:Cell Line, Tumor; D002465:Cell Movement; D016207:Cytokines / Q000096:biosynthesis*; D042783:Endothelial Cells / Q000378:metabolism*; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D006162:Guanylate Cyclase / Q000378:metabolism; D006801:Humans; D008297:Male; D008954:Models, Biological; D009569:Nitric Oxide / Q000378:metabolism*; D011471:Prostatic Neoplasms / Q000378:metabolism*; D054633:Receptor-Like Protein Tyrosine Phosphatases, Class 5 / Q000096:biosynthesis*
D002352:Carrier Proteins; D016207:Cytokines; C066845:pleiotrophin; D009569:Nitric Oxide; D054633:Receptor-Like Protein Tyrosine Phosphatases, Class 5; D006162:Guanylate Cyclase