Effect of GnRH analogs on the expression of TrkA and p75 neurotrophin receptors in primary cell cultures from human prostate adenocarcinoma.
BACKGROUND
GnRH analogs have antiproliferative and/or apoptotic effects on prostate cancer cells. Also, neurotrophin receptors TrkA and p75 have been reported in normal prostate suggesting a role in the gland growth control. In prostate cancer, TrkA receptors seem to be overexpressed and p75 receptors show a decreased expression. These changes in neurotrophin receptors may be related with unbalanced growth in malignant cells. In the present study we investigate the effects of GnRH analogs (leuprolide and cetrorelix) on the expression of TrkA and p75 neurotrophin receptors in primary cultures of human prostate cancer cells.


METHODS
Tissue was obtained from radical prostatectomies due to prostate adenocarcinoma. Cells were isolated after sequential enzyme digestion and cultured in defined media. Nerve growth factor (NGF) receptors in untreated cultures were estimated by immunofluorescence. Cultures were treated with leuprolide (agonist) or cetrorelix (antagonist) and expression of TrkA and p75 receptors were evaluated by semi quantitative RT-PCR (polymerase chain reaction) and western blot. Cell proliferation was estimated by MTT method and apoptosis through COMET assay.


RESULTS
Both leuprolide and cetrorelix induced a significant increase in p75 receptor gene and protein expression at a concentration that induce apoptosis and decrease proliferation. TrkA receptors showed no changes in presence of GnRH analogs.


CONCLUSIONS
GnRH analogs, leuprolide, and cetrorelix, change the ratio between neurotrophin receptors TrkA and p75 by increasing gene and protein expression of p75 receptor. Considering that TrkA receptor is related with proliferation and p75 with apoptosis, we suggest that our findings may explain, in part, the effect of GnRH analogs on prostate cancer growth.
Sánchez
Catherine
C
Physiology and Biophysics Program, Institute of Biomedical Sciences, Faculty of Medicine, University of Chile, Santiago, Chile.
Clementi
Marisa
M
Benitez
Dixan
D
Contreras
Héctor
H
Huidobro
Christian
C
Castellón
Enrique
E
D000230:Adenocarcinoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects; D020552:Comet Assay; D004847:Epithelial Cells / Q000473:pathology; D005562:Formazans / Q000737:chemistry; D007987:Gonadotropin-Releasing Hormone / Q000031:analogs & derivatives* / Q000494:pharmacology; D006801:Humans; D016729:Leuprolide / Q000494:pharmacology*; D008297:Male; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D020800:Receptor, Nerve Growth Factor; D020917:Receptor, trkA / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D017475:Receptors, Nerve Growth Factor / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013778:Tetrazolium Salts / Q000737:chemistry
D018931:Antineoplastic Agents, Hormonal; D005562:Formazans; D020800:Receptor, Nerve Growth Factor; D017475:Receptors, Nerve Growth Factor; D013778:Tetrazolium Salts; C079782:MTT formazan; D007987:Gonadotropin-Releasing Hormone; D020917:Receptor, trkA; D016729:Leuprolide; C062876:cetrorelix