Growth hormone (GH) receptors in prostate cancer: gene expression in human tissues and cell lines and characterization, GH signaling and androgen receptor regulation in LNCaP cells

Various hormones and growth factors have been implicated in progression of prostate cancer, but their role and the underlying molecular mechanism(s) involved remain poorly understood. In this study, we investigated the role of human growth hormone (GH) and its receptor (GHR) in human prostate cancer...

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Published in:	Molecular and cellular endocrinology Vol. 220; no. 1; pp. 109 - 123
Main Authors:	Weiss-Messer, Esther, Merom, Osnat, Adi, Ayala, Karry, Rachel, Bidosee, Maslama, Ber, Rosalie, Kaploun, Alexander, Stein, Avi, Barkey, Ronnie J
Format:	Journal Article
Language:	English
Published:	Ireland Elsevier Ireland Ltd 31-05-2004
Subjects:	Androgen receptor Animals Cattle Cell Line, Tumor DNA-Binding Proteins - metabolism Dose-Response Relationship, Drug DU145 cells Gene Expression Regulation, Neoplastic - drug effects GH receptors Growth Hormone - pharmacology Humans Janus Kinase 2 LNCaP cells Male Milk Proteins - metabolism Mitogen-Activated Protein Kinase 1 - metabolism Mitogen-Activated Protein Kinase 3 - metabolism Molecular Weight PC3 cells Phosphorylation - drug effects Phosphotyrosine - metabolism Prostate cancer Prostate-Specific Antigen - secretion Prostatic Neoplasms - genetics Prostatic Neoplasms - metabolism Prostatic Neoplasms - pathology Prostatic Neoplasms - secretion Protein Isoforms - genetics Protein Isoforms - metabolism Protein-Serine-Threonine Kinases - metabolism Protein-Tyrosine Kinases - metabolism Proto-Oncogene Proteins - metabolism Proto-Oncogene Proteins c-akt Receptors, Androgen - metabolism Receptors, Somatotropin - genetics Receptors, Somatotropin - metabolism RNA, Messenger - metabolism Signal transduction Signal Transduction - drug effects STAT5 Transcription Factor Substrate Specificity Testosterone Congeners - pharmacology Time Factors Trans-Activators - metabolism Tumor Suppressor Proteins GH receptors Signal transduction LNCaP cells DU145 cells Androgen receptor Prostate cancer PC3 cells
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Summary:	Various hormones and growth factors have been implicated in progression of prostate cancer, but their role and the underlying molecular mechanism(s) involved remain poorly understood. In this study, we investigated the role of human growth hormone (GH) and its receptor (GHR) in human prostate cancer. We first demonstrated mRNA expression of GHR and of its exon 9-truncated isoform (GHR tr) in benign prostate hyperplasia (BPH) and prostate adenocarcinoma patient tissues, as well as in LNCaP, PC3 and DU145 human prostate cancer cell lines. GHR mRNA levels were 80% higher and GHR tr only 25% higher, in the carcinoma tissues than in BPH. Both isoforms were also expressed in LNCaP and PC3 cell lines and somewhat less so in DU145 cells. The LNCaP cell GHR protein was further characterized, on the basis of its M r of 120 kDa, its binding to two different GHR monoclonal antibodies, its high affinity and purely somatogenic binding to 125I-hGH and its ability to secrete GH binding protein, all characteristic of a functional GHR. Furthermore, GH induced rapid, time- and dose-dependent signaling events in LNCaP cells, including phosphorylation of JAK2 tyrosine kinase, of GHR itself and of STAT5A (JAK2-STAT5A pathway), of p42/p44 MAPK and of Akt/PKB. No effect of GH (72 h) could be shown on basal or androgen-induced LNCaP cell proliferation nor on PSA secretion. Interestingly, however, GH caused a rapid (2–12 h) though transient striking increase in immunoreactive androgen receptor (AR) levels (≤5-fold), followed by a slower (24–48 h) reduction (≤80%), with only modest parallel changes in serine-phosphorylated AR. In conclusion, the GH-induced activation of signaling pathways, its effects on AR protein in LNCaP cells and the isoform-specific regulation of GHR in prostate cancer patient tissues, suggest that GH, most likely in concert with other hormones and growth factors, may play an important role in progression of human prostate cancer.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0303-7207 1872-8057
DOI:	10.1016/j.mce.2004.03.004