Antagonists of growth hormone-releasing hormone inhibit the proliferation of human benign prostatic hyperplasia cells.
BACKGROUND
Growth hormone-releasing hormone (GHRH), besides stimulating the secretion of GH from the pituitary gland, acts as an autocrine/paracrine growth factor in many cancers. Antagonists of GHRH inhibit growth of experimental human tumors, but their effects on benign prostatic hyperplasia (BPH) have not been studied.


METHODS
We evaluated the effects of GHRH and GHRH antagonists JMR-132, MZ-5-156, MIA-601, and MIA-479 on the proliferation rate of human BPH-1 cells. We also measured by Western blot the influence of GHRH and GHRH antagonist JMR-132 on the expression of the PCNA and the activation of ERK1/2 and JAK/STAT3.


RESULTS
BPH-1 cells express GHRH and GHRH-receptor proteins. The proliferation rate of BPH-1 cells is increased by GHRH and inhibited by all the GHRH antagonists, the latest analogs MIA-601 and MIA-479 being the most potent. The stimulatory effect of GHRH is nullified by GHRH antagonists. GHRH strongly activates and GHRH antagonists significantly suppress the expression of the PCNA and the phosphorylation of ERK1/2 and JAK2/STAT3 pathways in these cells. Treatment with JAK2 inhibitor (AG490) decreases the proliferation rate of BPH-1 cells, and AG490 does nullify the effect of GHRH.


CONCLUSIONS
This study demonstrates for the first time that GHRH can act as a growth factor in BPH-1 cells and that GHRH antagonists can reverse its stimulatory effect. New observations are provided on the mechanism of action of GHRH antagonists in BPH. Our findings support the merit of further work on the development of GHRH antagonists for therapy of BPH.
Veterans Affairs Medical Center and South Florida Veterans Affairs Foundation for Research and Education, Miami, Florida.
Agnieszka
A
Siejka
Andrew V
AV
Schally
Norman L
NL
Block
Nektarios
N
Barabutis
D015153:Blotting, Western; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D013007:Growth Hormone-Releasing Hormone / Q000037:antagonists & inhibitors*; D006367:HeLa Cells; D006801:Humans; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D008297:Male; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D018809:Proliferating Cell Nuclear Antigen / Q000096:biosynthesis; D011470:Prostatic Hyperplasia / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology*; D050796:STAT3 Transcription Factor / Q000378:metabolism; D017337:Sermorelin / Q000031:analogs & derivatives* / Q000494:pharmacology; D020032:Tyrphostins / Q000494:pharmacology
D004791:Enzyme Inhibitors; C534070:GHRH(1-29)NH2, PhAcTyr(1)-Arg(2)-P(H)e(4-CL)(6)-Ala(8)-Tyr(Me)(10)-His(11)-Abu(15)-His(20)-Nle(27)-Arg(28)-HLCr(29)-; D018809:Proliferating Cell Nuclear Antigen; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D020032:Tyrphostins; C095512:alpha-cyano-(3,4-dihydroxy)-N-benzylcinnamide; D017337:Sermorelin; D013007:Growth Hormone-Releasing Hormone; C507924:JAK2 protein, human; D053614:Janus Kinase 2; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3