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

Autor: Avi Stein, Rachel Karry, Osnat Merom, Maslama Bidosee, Rosalie Ber, R. J. Barkey, Ayala Adi, Esther Weiss-Messer, Alexander Kaploun
Rok vydání: 2004
Předmět:
Male
Time Factors
Growth hormone receptor
urologic and male genital diseases
Biochemistry
Substrate Specificity
Prostate cancer
Endocrinology
Growth hormone-binding protein
STAT5 Transcription Factor
Protein Isoforms
Phosphorylation
Receptor
Testosterone Congeners
Mitogen-Activated Protein Kinase 1
Mitogen-Activated Protein Kinase 3
Protein-Tyrosine Kinases
Milk Proteins
DNA-Binding Proteins
Gene Expression Regulation
Neoplastic
Receptors
Androgen
hormones
hormone substitutes
and hormone antagonists
Signal Transduction
medicine.medical_specialty
Protein Serine-Threonine Kinases
Biology
DU145
Cell Line
Tumor
Proto-Oncogene Proteins
Internal medicine
LNCaP
medicine
Animals
Humans
RNA
Messenger
Phosphotyrosine
Molecular Biology
Protein kinase B
Dose-Response Relationship
Drug
Tumor Suppressor Proteins
Prostatic Neoplasms
Receptors
Somatotropin
Janus Kinase 2
Prostate-Specific Antigen
medicine.disease
Molecular Weight
Androgen receptor
Growth Hormone
Trans-Activators
Cancer research
Cattle
Proto-Oncogene Proteins c-akt
Zdroj: Molecular and Cellular Endocrinology. 220:109-123
ISSN: 0303-7207
DOI: 10.1016/j.mce.2004.03.004
Popis: 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 120kDa, its binding to two different GHR monoclonal antibodies, its high affinity and purely somatogenic binding to (125)I-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 (72h) could be shown on basal or androgen-induced LNCaP cell proliferation nor on PSA secretion. Interestingly, however, GH caused a rapid (2-12h) though transient striking increase in immunoreactive androgen receptor (AR) levels (< or =5-fold), followed by a slower (24-48h) reduction (< or = 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.
Databáze: OpenAIRE
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