Effect of GHRH and peptides from the vasoactive intestinal peptide family on cAMP production of human cancer cell lines in vitro

Antagonistic analogs of GHRH inhibit growth of various human cancers both i n vivo and in vitro. To elucidate the mechanism of direct action of the ant agonistic analogs of GHRH on turner cells, cultured human cancer cells were exposed to GHRH, vasoactive intestinal peptide (VIP), secretin, glucagon, neuropeptide-Y (NPY), pituitary adenylate cyclase-activating peptide (PACAP ), and VIP analogs in a superfusion system, and changes in cAMP and IGF-II release from the cells were measured. Various human cancer cell lines, such as mammary (MDA-MB-468 and ZR-75-1), prostatic (PC-3), pancreatic (SW-1990 and Capan-2), ovarian (OV-1063), and colorectal (LoVo) responded to pulsat ile stimuli with GHRH (0.5-20 nM), VIP (0.02-10 nM), and PACAP-38 (0.05-5 n M) with a rapid, transient increase in cAMP release from the cells. The VIP antagonist, PG-97-269, and the adenylate cyclase inhibitor, MDL-12330A, bu t not SQ-22536 or pertussis toxin, blocked the cAMP responses to these pept ides. Stimulation of the cells with 100 nM secretin, glucagon or NPY did no t alter the cAMP release. Our results suggest that GHRH receptors different from the type expressed in the pituitary are involved in mediating these e ffects. As cAMP is a potent second messenger controlling a wide variety of intracellular functions, including those required for cell growth, our resu lts indicate that GHRH might have a direct stimulatory effect on growth of human cancers. Blockade of the autocrine/paracrine action of GHRH with its antagonistic analogs may provide a new approach to tumor control.