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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.

Abstract

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.

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  • Authors+Show Affiliations

    ,

    Department of Pharmacology, Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Technion, P.O.B. 9649, Haifa 31096, Israel.

    , , , , , , ,

    Source

    Molecular and cellular endocrinology 220:1-2 2004 May 31 pg 109-23

    MeSH

    Animals
    Cattle
    Cell Line, Tumor
    DNA-Binding Proteins
    Dose-Response Relationship, Drug
    Gene Expression Regulation, Neoplastic
    Growth Hormone
    Humans
    Janus Kinase 2
    Male
    Milk Proteins
    Mitogen-Activated Protein Kinase 1
    Mitogen-Activated Protein Kinase 3
    Molecular Weight
    Phosphorylation
    Phosphotyrosine
    Prostate-Specific Antigen
    Prostatic Neoplasms
    Protein Isoforms
    Protein-Serine-Threonine Kinases
    Protein-Tyrosine Kinases
    Proto-Oncogene Proteins
    Proto-Oncogene Proteins c-akt
    RNA, Messenger
    Receptors, Androgen
    Receptors, Somatotropin
    STAT5 Transcription Factor
    Signal Transduction
    Substrate Specificity
    Testosterone Congeners
    Time Factors
    Trans-Activators
    Tumor Suppressor Proteins

    Pub Type(s)

    Journal Article
    Research Support, Non-U.S. Gov't

    Language

    eng

    PubMed ID

    15196705

    Citation

    Weiss-Messer, Esther, et al. "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." Molecular and Cellular Endocrinology, vol. 220, no. 1-2, 2004, pp. 109-23.
    Weiss-Messer E, Merom O, Adi A, et al. 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. Mol Cell Endocrinol. 2004;220(1-2):109-23.
    Weiss-Messer, E., Merom, O., Adi, A., Karry, R., Bidosee, M., Ber, R., ... Barkey, R. J. (2004). 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. Molecular and Cellular Endocrinology, 220(1-2), pp. 109-23.
    Weiss-Messer E, et al. 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. Mol Cell Endocrinol. 2004 May 31;220(1-2):109-23. PubMed PMID: 15196705.
    * Article titles in AMA citation format should be in sentence-case
    TY - JOUR T1 - 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. AU - Weiss-Messer,Esther, AU - Merom,Osnat, AU - Adi,Ayala, AU - Karry,Rachel, AU - Bidosee,Maslama, AU - Ber,Rosalie, AU - Kaploun,Alexander, AU - Stein,Avi, AU - Barkey,Ronnie J, PY - 2004/01/26/received PY - 2004/03/03/revised PY - 2004/03/12/accepted PY - 2004/6/16/pubmed PY - 2005/1/13/medline PY - 2004/6/16/entrez SP - 109 EP - 23 JF - Molecular and cellular endocrinology JO - Mol. Cell. Endocrinol. VL - 220 IS - 1-2 N2 - 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. SN - 0303-7207 UR - https://www.unboundmedicine.com/medline/citation/15196705/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_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0303720704001017 DB - PRIME DP - Unbound Medicine ER -