Cholera toxin inhibits signal transduction by several mitogens and the in vitro growth to human small-cell lung cancer

• Published in: The Journal of clinical investigation Vol. 86; no. 6; pp. 1904 - 1912
• Main Authors: VIALLET, J, SHARONI, Y, FRUCHT, H, JENSEN, R. T, MINNA, J. D, SAUSVILLE, E. A
• Format: Journal Article
• Language: English
• Published: Ann Arbor, MI American Society for Clinical Investigation 01.12.1990
• Subjects: Adenosine Diphosphate Ribose - metabolism; Adenylyl Cyclases - metabolism; Biological and medical sciences; Bombesin - pharmacology; Calcium - metabolism; Carcinoma, Small Cell - pathology; Cell Division - drug effects; Cell Membrane - drug effects; Cell Membrane - ultrastructure; Cholera Toxin - pharmacology; Colforsin - pharmacology; Dose-Response Relationship, Drug; Fundamental and applied biological sciences. Psychology; G(M1) Ganglioside - metabolism; Growth Inhibitors; GTP-Binding Proteins - metabolism; Humans; In Vitro Techniques; Ionomycin - pharmacology; Mitogens - pharmacology; Molecular and cellular biology; Molecular genetics; Receptors, Bombesin; Receptors, Neurotransmitter - physiology; Signal Transduction - drug effects; Time Factors; Tumor Cells, Cultured; Vasopressins - pharmacology; Signal transduction; Enzyme; Cyclic AMP; Molecular biology; Non small cell carcinoma; Growth factor; Phospholipase C; G protein
• ISSN: 0021-9738; 1558-8238
• DOI: 10.1172/JCI114923

Cholera toxin (CT) inhibited the in vitro growth of three of four human small-cell lung carcinoma (SCLC) cell lines with a 50% inhibitory concentration of 27-242 ng/ml. Loss of surface membrane ruffling and the capacity of [Tyr4]-bombesin, vasopressin, and fetal calf serum to stimulate increases in intracellular free calcium clearly preceded effects on cellular metabolic activity and cell growth. 125I-[Tyr4]-bombesin binding was unaffected by CT treatment but [Tyr4]-bombesin stimulated phospholipase C activity was decreased in membranes from CT-treated SCLC cells. CT stimulated a rapid but transient increase in intracellular cyclic AMP ([cAMP]i) in SCLC. The effects of CT on susceptible SCLC were not reproduced by elevations of [cAMP]i induced by forskolin or cyclic AMP analogues. GM1 ganglioside, the cellular binding site for CT, was highly expressed in the CT-sensitive but not the CT-resistant SCLC cell lines. In contrast, expression of guanine nucleotide binding protein substrates for ADP-ribosylation by CT was similar. These data demonstrate the existence of a CT-sensitive growth inhibitory pathway in SCLC-bearing GM1 ganglioside. Addition of CT results in decreased responsiveness to several mitogenic stimuli. These results suggest novel therapeutic approaches to human SCLC.