DIFFERENTIAL GROWTH-REGULATION OF A METASTATIC HUMAN LUNG-CARCINOMA CELL-LINE THROUGH ACTIVATION OF PHOSPHATIDYL-INOSITOL TURNOVER SIGNAL-TRANSDUCTION PATHWAY

Until recently, the signal transduction pathways involved in the proce sses of tumor growth have been poorly understood. In the present study , we investigated cell surface receptors which utilize phosphatidylino sitol (P1) turnover/Ca2+ mobilization as a signal transduction pathway to regulate cell growth in a metastatic human lung carcinoma cell lin e, PG. We found that purinoceptor agonists, including ATP and its anal ogs, and bombesin, an amphibian tetradeca-peptide of mammalian homolog y gastrin-releasing peptide, induced rapid transient increase of cytop lasmic-free Ca2+ in PG cells loaded with fura-2. The Ca2+ responses we re derived both from release from internal stores and the opening of p lasma membrane Ca2+ channels. HPLC analysis of inositol 1,4,5-triphosp hate (Ins(1,4,5)P3) and its isomers showed a receptor-linked phospholi pase C activation by ATP and bombesin. Although ATP and bombesin were both able to induce P1 turnover and Ca2+ mobilization in PG cells, the y had differential growth regulatory effects on PG cells. Treatment wi th bombesin stimulated PG cell growth while treatment with ATP inhibit ed significantly PG cell growth. Pharmacological studies showed that t he purinoceptors on PG cells were of the P2 subtype. Other hydrolysis- resistant P2 purinoceptor agonists, including ATPgammaS and AMP-PNP, w ere as effective as ATP in stimulating P1 turnover and Ca2+ mobilizati on as well as in inhibiting PG cell growth in vitro, suggesting the po tential usefulness of such ATP analogs in clinical trials. Preliminary results suggest G protein involvement in the differential regulation of ATP and bombesin signal transduction pathways.