Original Article
Co-expression of GH and GHR isoforms in prostate cancer cell lines

https://doi.org/10.1054/ghir.2002.0271Get rights and content

Abstract

Prostate cancer is a significant cause of morbidity and mortality in Western males. While it is known that androgens play a central role in prostate cancer development and progression, other hormones and growth factors are also involved in prostate growth. Insulin-like growth factor-I (IGF-I) plasma levels have been associated with prostate cancer risk, and growth hormone (GH), a major factor regulating IGF levels, also appears to have a role in prostate cancer cell growth. Most significantly, GH has been shown to increase the rate of cell proliferation in prostate cancer cell lines. We have now demonstrated the co-expression of GH and GH receptor (GHR) mRNA isoforms in the ALVA41, PC3, DU145, LNCaP prostate cancer cells by reverse transcription polymerase chain reaction. Sequence analysis has confirmed that these cell lines express the pituitary form of GH mRNA and also the placental mRNA isoform. These prostate cancer cell lines also express the full-length mRNA for the GHR and the exon 3 deleted isoform. We have also demonstrated the presence of GH and GHR proteins in these cell lines by immunohistochemistry. GH expression has not been described previously in human prostate cancer cells. The co-expression of GH and its receptor would enable an autocrineā€“paracrine pathway to exist in the prostate that would be capable of stimulating prostate growth, either directly via the GHR or indirectly via IGF production. The GH axis in the prostate could therefore be an important additional target for the future development of prostate cancer therapies.

References (58)

  • W.L. McKeehan et al.

    Direct mitogenic effects of insulin, epidermal growth factor, glucocorticoid, cholera toxin, unknown pituitary factors and possibly prolactin, but not androgen, on normal rat prostate epithelial cells in serum-free, primary cell culture

    Cancer Res

    (1984)
  • J. Chan et al.

    Plasma insulin-like growth factor-I and prostate cancer risk: a prospective study

    Science

    (1998)
  • T. Shaneyfelt et al.

    Hormonal predictors of prostate cancer: a meta-analysis

    J Clin Oncol

    (2000)
  • C. Cutting et al.

    Serum insulin-like growth factor 1 is not a useful marker of prostate cancer

    Br J Urol Int

    (1999)
  • E. Reiter et al.

    Growth hormone directly affects the function of the different lobes of the rat prostate

    Endocrinology

    (1995)
  • F. Sinowatz et al.

    Growth hormone receptor expression in the Dunning R 3327 prostatic carcinoma of the rat

    Prostate

    (1991)
  • W. Ruan et al.

    Evidence that insulin-like growth factor I and growth hormone are required for prostate gland development

    Endocrinology

    (1999)
  • J.C. Prieto et al.

    Growth hormone binding and stimulation of amino acid uptake in epithelial cells of rat ventral prostate

    Cell Biochem Funct

    (1987)
  • P.E. Lobie et al.

    Cellular localization of the growth hormone receptor/binding protein in the male and female reproductive systems

    Endocrinology

    (1990)
  • S. Koelle et al.

    Expression of growth hormone receptor in human prostatic carcinoma and hyperplasia

    Int J Oncol

    (1999)
  • A.C. Herington et al.

    Growth hormone binding proteins

  • R. Kineman

    Antitumorigenic actions of growth hormone releasing hormone antagonists

    Proc Natl Acad Sci USA

    (2000)
  • L.K. Chopin et al.

    GHRH. A potential autocrine pathway for growth hormone releasing hormone (GHRH) and its receptor in human prostate cancer cell lines

    Prostate

    (2001)
  • C. Boguszewski et al.

    Cloning of two novel growth hormone transcripts expressed in human placenta

    J Clin Endocrinol Metab

    (1998)
  • N. Cooke et al.

    Human growth hormone gene expression in pituitary and placenta

    Human Growth Hormone Pharmacology: Basic and Clinical Aspects

    (1995)
  • M. Ballesteros et al.

    Distribution and abundance of messenger ribonucleic acid for growth hormone receptor isoforms in human tissues

    J Clin Endocrinol Metab

    (2000)
  • K. Tokunaga et al.

    Nucleotide sequence of a full-length cDNA for mouse cytoskeletal beta-actin mRNA

    Nucl Acids Res

    (1986)
  • R. Barnard et al.

    Characterization of the growth hormone-binding protein of human serum using a panel of monoclonal antibodies

    J Endocrinol

    (1989)
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    L.K. Chopin, Centre for Molecular Biotechnology, Queensland University of Technology, GPO Box 2434, Brisbane, Q 4001, Australia. Tel: +61 7 38642667; Fax: +61 7 3864 1534; E-mail: [email protected]

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