Signaling and antiproliferative effects of type I and II gonadotropin-releasing hormone receptors in breast cancer cells.
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.
Finch
Ann R
AR
Wellcome Laboratories for Integrative Neuroscience and Endocrinology, University of Bristol, Bristol, BS1 3NY, United Kingdom.
Green
Lisa
L
Hislop
James N
JN
Kelly
Eamonn
E
McArdle
Craig A
CA
D000818:Animals; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology*; D002064:Buserelin / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D002678:Chimera; D005260:Female; D018014:Gene Transfer Techniques; D006801:Humans; D008968:Molecular Conformation; D010446:Peptide Fragments / Q000737:chemistry / Q000378:metabolism; D011966:Receptors, LHRH / Q000235:genetics / Q000378:metabolism*; D012756:Sheep; D015398:Signal Transduction; D013045:Species Specificity; D014982:Xenopus laevis
D018931:Antineoplastic Agents, Hormonal; C484844:GNRHR protein, human; C427484:GNRHR2 protein, human; D010446:Peptide Fragments; D011966:Receptors, LHRH; D002064:Buserelin