Abstract
GnRH receptors (GnRH-Rs) mediate direct antiproliferative effects on hormone-dependent cancer cells. GnRH-Rs can be grouped according to ligand specificity (for GnRH-I and -II), and there is evidence that type II GnRH ligands and/or receptors can inhibit proliferation. Type I GnRH-Rs (e.g. human and sheep) lack the C-terminal tails found in other G protein-coupled receptors including type II GnRH-Rs (e.g. Xenopus; XGnRH-R). This underlies the remarkable resistance of type I GnRH-Rs to desensitization and may be important for chronic effects on proliferation. To test this, we have compared the antiproliferative effects of GnRH-Rs expressed in MCF7 breast cancer cells using recombinant adenovirus (Ad). Endogenous GnRH-Rs were not detected, but infection with Ad-expressing sheep GnRH-Rs (sGnRH-R) facilitated proliferation inhibition by Buserelin, and maximum inhibition required only 10,000-20,000 sGnRH-Rs. XGnRH-Rs were much less efficient at inhibiting proliferation and were internalized faster than sGnRH-Rs. Thus, the type II GnRH-R is less efficient at inhibiting proliferation, presumably because it is rapidly desensitized and/or internalized. Moreover, comparisons of human GnRH-R, sGnRH-R, and XGnRH-R, as well as chimeric receptors (type I GnRH-Rs with C-terminal tails from XGnRH-Rs), revealed that C-terminal tail addition increases receptor expression and thereby increases the efficiency with which the vector facilitates the antiproliferative effect.
Original language | English |
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Pages (from-to) | 1823-32 |
Number of pages | 10 |
Journal | Journal of Clinical Endocrinology and Metabolism |
Volume | 89 |
Issue number | 4 |
DOIs | |
Publication status | Published - Apr 2004 |
Keywords
- Animals
- Antineoplastic Agents, Hormonal
- Breast Neoplasms
- Buserelin
- Cell Division
- Cell Line, Tumor
- Chimera
- Female
- Gene Transfer Techniques
- Humans
- Molecular Conformation
- Peptide Fragments
- Receptors, LHRH
- Sheep
- Signal Transduction
- Species Specificity
- Xenopus laevis