Cholera toxin inhibits signal transduction by several mitogens and the in vitro growth of human small-cell lung cancer.
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.
Viallet
J
J
National Cancer Institute-Navy Medical Oncology Branch, Bethesda, Maryland.
Sharoni
Y
Y
Frucht
H
H
Jensen
R T
RT
Minna
J D
JD
Sausville
E A
EA
D000246:Adenosine Diphosphate Ribose / Q000378:metabolism; D000262:Adenylyl Cyclases / Q000378:metabolism; D001839:Bombesin / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D018288:Carcinoma, Small Cell / Q000473:pathology*; D002455:Cell Division / Q000187:drug effects; D002462:Cell Membrane / Q000187:drug effects / Q000648:ultrastructure; D002772:Cholera Toxin / Q000494:pharmacology*; D005576:Colforsin / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005677:G(M1) Ganglioside / Q000378:metabolism; D019204:GTP-Binding Proteins / Q000378:metabolism; D006131:Growth Inhibitors; D006801:Humans; D066298:In Vitro Techniques; D015759:Ionomycin / Q000494:pharmacology; D008934:Mitogens / Q000494:pharmacology*; D018004:Receptors, Bombesin; D017981:Receptors, Neurotransmitter / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects*; D013997:Time Factors; D014407:Tumor Cells, Cultured; D014667:Vasopressins / Q000494:pharmacology
D006131:Growth Inhibitors; D008934:Mitogens; D018004:Receptors, Bombesin; D017981:Receptors, Neurotransmitter; D014667:Vasopressins; D005576:Colforsin; D000246:Adenosine Diphosphate Ribose; D005677:G(M1) Ganglioside; D015759:Ionomycin; D002772:Cholera Toxin; D019204:GTP-Binding Proteins; D000262:Adenylyl Cyclases; D001839:Bombesin; D002118:Calcium