Inhibition of human androgen-independent PC-3 and DU-145 prostate cancers by antagonists of bombesin and growth hormone releasing hormone is linked to PKC, MAPK and c-jun intracellular signalling.
Bombesin/gastrin-releasing peptide (BN/GRP) antagonists RC-3940-II and RC-3940-Et, and growth hormone-releasing hormone (GHRH) antagonists MZ-J-7-118 and RC-J-29-18 inhibit the growth of human androgen-independent PC-3 and DU-145 prostate cancers in nude mice. Additive inhibitory effects were observed after treatment with both classes of analogs. In the present study, we investigated the effects of these antagonists on intracellular signalling pathways of protein kinase C (PKC), mitogen activated protein kinases (MAPK) and c-fos and c-jun oncogenes that are involved in tumour cell proliferation. In PC-3 tumours, antagonists of BN/GRP and GHRH decreased significantly the expression of PKC isoforms alpha (alpha), eta (eta) and zeta (zeta) and increased that of delta (delta) PKC protein. MAPK was not detectable. In DU-145 tumours, which constitutively express MAPK, all treatments strongly decreased the levels of p42/44 MAPK. Treatment with the antagonists tended to reduce m-RNA for c-jun in both tumour models. In proliferation assays in vitro, inhibitors of PKC and MAPK diminished growth of DU-145 and PC-3 cells. These findings suggest that antagonists of BN/GRP and GHRH inhibit the growth of androgen-independent prostate cancer by affecting intracellular signalling mechanisms of PKC, MAPK and c-jun.
Stangelberger
Anton
A
Endocrine, Polypeptide and Cancer Institute, Veterans Affairs Medical Center, 1601 Perdido St., New Orleans, LA 70112-1262, USA.
Schally
Andrew V
AV
Varga
Jozsef L
JL
Zarandi
Marta
M
Cai
Ren-Zhi
RZ
Baker
Benjamin
B
Hammann
Brian D
BD
Armatis
Patricia
P
Kanashiro
Celia A
CA
D000704:Analysis of Variance; D015153:Blotting, Western; D001839:Bombesin / Q000037:antagonists & inhibitors*; D002450:Cell Communication; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D016762:Genes, fos / Q000502:physiology; D016758:Genes, jun / Q000502:physiology*; D013007:Growth Hormone-Releasing Hormone / Q000037:antagonists & inhibitors*; D006801:Humans; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D011493:Protein Kinase C / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction
D009363:Neoplasm Proteins; D013007:Growth Hormone-Releasing Hormone; D011493:Protein Kinase C; D020928:Mitogen-Activated Protein Kinases; D001839:Bombesin