Different signal responses to Lamprey GnRH-III in human cancer cells

Analogs of GnRH used for the treatment of sex steroid-independent tumors are not optimal because of endocrine side-effects. Lamprey gonadotropin-releasing hormone III (lGnRH-III), however, directly inhibits the growth of several tumor cell lines derived from reproductive organs. In this study, the signaling and antiproliferative effects of lGnRH-III on two breast, a colonic and a pancreatic cancer cell lines were investigated. Binding affinity of the peptide was determined by competitive receptor binding assays. Cell proliferation was measured following treatment for 3 days with lGnRH-III. Intracellular cAMP levels in response to lGnRH-III binding were quantified and effects of pertussis toxin (PTX), an inhibitor of G(i) activation, on suppression of growth by lGnRH-III were examined. lGnRH-III had comparable affinities for receptors on all four cell lines and inhibited their growth at micromolar concentrations in a dose-dependent manner. PTX-sensitive decrease in cAMP levels in response to lGnRH-III in colonic and pancreatic cells was observed, while lGnRH-III increased intracellular [Ca2+] in both breast cancer cell lines. This study further indicates that the same receptors utilize different signal transduction pathways in different cancer cells.