Antiproliferative actions of growth hormone-releasing hormone antagonists on MiaPaCa-2 human pancreatic cancer cells involve cAMP independent pathways.
We evaluated the effects of GHRH antagonists on the proliferation of MiaPaCa-2 human pancreatic cancer cells and cAMP signaling in vitro. GHRH antagonists inhibited the proliferation of MiaPaCa-2 cells in vitro in a dose-dependent way and caused a significant elevation in cAMP production. In a superfusion system, short-term exposure of the cells to GHRH antagonists evoked an acute, dose-dependent release of cAMP into the medium. Native GHRH, which stimulates cAMP efflux from pituitary at nanomolar doses, did not influence cAMP release from cultured or superfused MiaPaCa-2 cells even at 10-30 microM. VIP, PACAP, secretin and glucagon also did not influence cell proliferation or cAMP production. Adenylate cyclase activator forskolin (FSK) caused a greater cAMP response, but a smaller antiproliferative effect than GHRH antagonists. Combined treatment with FSK and GHRH antagonist JV-1-38 potentiated the cAMP-inducing effect of FSK, but did not produce a greater inhibition of cell proliferation than JV-1-38 alone. A selective accumulation of radiolabeled GHRH antagonist [(125)I]JV-1-42 in vivo in MiaPaCa-2 carcinoma xenografted into nude mice was also observed. In conclusion, second messengers other than cAMP participate in the signal transduction pathways of GHRH analogs mediated by tumoral GHRH receptors.
Rekasi
Z
Z
Endocrine, Polypeptide and Cancer Institute, Veterans Affairs Medical Center, New Orleans, LA 70112, USA.
Varga
J L
JL
Schally
A V
AV
Plonowski
A
A
Halmos
G
G
Csernus
B
B
Armatis
P
P
Groot
K
K
D000262:Adenylyl Cyclases / Q000378:metabolism; D000818:Animals; D002455:Cell Division / Q000187:drug effects; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D005934:Glucagon / Q000494:pharmacology; D013007:Growth Hormone-Releasing Hormone / Q000037:antagonists & inhibitors*; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009132:Muscles / Q000378:metabolism; D009368:Neoplasm Transplantation; D009479:Neuropeptides / Q000494:pharmacology; D010190:Pancreatic Neoplasms / Q000378:metabolism*; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; D011863:Radioimmunoassay; D012633:Secretin / Q000494:pharmacology; D015398:Signal Transduction; D014407:Tumor Cells, Cultured; D014660:Vasoactive Intestinal Peptide / Q000494:pharmacology
C495401:ADCYAP1 protein, human; C495402:Adcyap1 protein, mouse; D009479:Neuropeptides; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; D012633:Secretin; D005576:Colforsin; D014660:Vasoactive Intestinal Peptide; D005934:Glucagon; D013007:Growth Hormone-Releasing Hormone; D000242:Cyclic AMP; D000262:Adenylyl Cyclases