G-PROTEIN EFFECTORS AS TARGETS FOR ANTINEOPLASTIC THERAPIES

bombesin样肽被认为是生长因子

Bombesin-like peptides have been implicated as growth factors for certain lung, breast, and prostate carcinoma cells. These peptides are known to transduce growth regulatory signals through guanine nucleotide binding proteins(G-proteins) to such effectors as phospholipases. Due to the heterogeneity of growth factor receptor expression, it is possible that the optimal therapeutic manipulation of this system will occur at the post-receptor level. To define more precisely the effectors of the bombesin-like peptide neuromedin-b(NMB)'s action, transfectants were created in which the rat NMB receptor (NMB-R)gene was introduced into Balb 3T3 cells which do not express bombesin peptide receptors. The resultant cell line, NMB-8, expresses 800,000 NMB binding sites/cell. Addition of NMB has a biphasic effect on [3H]thymidine([3H)dT) incorporation in confluent and quiescent cells: up to 10 nM of NMB causes a 1.5-3 fold stimulation of (3H]dT incorporation, but at greater than 10 NM there is clear inhibition of [3H)dT incorporation in response to ligand, and at 100 nM of NMB there was inhibition of cell growth. NMB causes protracted increases in intracellular Ca2+, as well as pertussis toxin(PT) - insensitive but guanosine5'-o-[3-thiotriphosphate]- stimulated increase in phospholipase-C activity. Arachidonate release was also activated by NMB in a PT-insensitive manner. Short term exposure to 12-tetradecanoyl-phorbol-13-acetate inhibited NMB-mediated phosphatidylinositol turnover but not arachidonate release. We conclude that NMB-R can promote [3H]dT incorporation, but that persistent activation of large numbers of receptors may inhibit cell growth perhaps related to the unregulated elaboration of second-messenger molecules. Additional studies have revealed that peptides modeled on the third intracytoplasmic loop of the neuromedin and bombesin receptors and on the wasp venom toxin mastoparan possess growth inhibitory properties for lung tumor cell lines. Whether the mechanism for these peptides' action proceeds through a modulation of G-protein action or through an alteration of the cell membrane in currently under study.