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Signaling events associated with gonadotropin releasing hormone‐agonist‐induced hormonal castration and its reversal in canines
Author(s) -
Bulldan Ahmed,
Shihan Mazen,
GoerickePesch Sandra,
ScheinerBobis Georgios
Publication year - 2016
Publication title -
molecular reproduction and development
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.745
H-Index - 105
eISSN - 1098-2795
pISSN - 1040-452X
DOI - 10.1002/mrd.22751
Subject(s) - biology , medicine , endocrinology , creb , agonist , castration , hormone , gonadotropin releasing hormone , phosphorylation , signal transduction , testosterone (patch) , apoptosis , receptor , transcription factor , microbiology and biotechnology , luteinizing hormone , gene , biochemistry
SUMMARY A gonadotropin‐releasing hormone agonist (GnRH‐A) implant induces hormonal castration in dogs that is associated with reduced prostate and testes size. We address the molecular events associated with hormonal castration by examining GnRH‐A effects on expression and phosphorylation of a number of key signaling proteins. Male beagles were treated for 5 months with a GnRH‐A implant, and then surgically castrated at 0, 3, 6, 12, and, 24 weeks after implant removal; untreated animals served as controls. GnRH‐A treatment led to activation of c‐Raf, Erk1/2, and, p53 in the testes. Phosphorylation of p53 occurred at Ser15, consistent with activation of the c‐Raf‐Erk1/2‐p53 signaling cascade that triggers growth arrest or apoptosis. GnRH‐A also suppressed the anti‐apoptotic protein Bcl‐xL; reduced phosphorylation of the transcription factors CREB and ATF1; and down‐regulated expression of StAR and P450scc, proteins involved in steroidogenesis. Although androgen receptor expression was little affected by GnRH‐A treatment, levels of ZIP9, a membrane‐bound Zn 2+ transporter that mediates non‐classical signaling of testosterone, were abrogated. All of these effects were reversed within 24 weeks after implant removal. Thus, molecular signatures of implant‐dependent hormonal castration include reversible cell cycle arrest and apoptosis, loss of steroidogenesis, and reduced transcriptional activity. Mol. Reprod. Dev. 83: 1092–1101, 2016. © 2016 Wiley Periodicals, Inc .