The regulation of mitogen stimulated signal transduction pathways in human lung cancer /

Established human lung cancer exhibits a complex pattern of genetic changes as well as several distinct autocrine growth factor loops for regulatory peptides. The best studied example is that of gastrin-releasing peptide or GRP, the mammalian homolog of the amphibian bombesin. Three human bombesin receptor subtypes have been cloned. They are the gastrin-releasing peptide receptor (GRP-R), the neuromedin-B receptor (NMB-R), and the bombesin-receptor subtype-3 (BRS-3). Low level expression of the GRP-R and NMB-R mRNA was detected in cultures of human bronchial epithelium. BRS-3 mRNA was undetected in these cells. An elevation of intracellular calcium concentration was observed in response to bradykinin, but not to bombesin, vasopressin or cholecystokinin. Such responses are frequently noted in lung cancer cell lines. This suggests that broad responsiveness to multiple neuropeptides is acquired during bronchial carcinogenesis. However, homologous desensitization of intracellular calcium responses to bombesin is present in lung cancer cells and can be mimicked by protein kinase C-activating phorbol esters. However, upon inhibition of protein kinase C, homologous desensitization to bombesin persists. The data indicate that protein kinase C is not a dominant component in the homologous desensitization to bombesin in small cell lung cancer cells