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

J. Viallet, Y. Sharoni, H. Frucht, R. T. Jensen, J. D. Minna, E. A. Sausville

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)1904-1912
Number of pages9
JournalJournal of Clinical Investigation
Volume86
Issue number6
StatePublished - Dec 1990

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Cholera Toxin
Small Cell Lung Carcinoma
Mitogens
Signal Transduction
Growth
Bombesin
G(M1) Ganglioside
In Vitro Techniques
Cell Line
Guanine Nucleotides
Membranes
Type C Phospholipases
Colforsin
Vasopressins
Cyclic AMP
Adenosine Diphosphate
Inhibitory Concentration 50
Carrier Proteins
Binding Sites
Calcium

Keywords

  • Cyclic adenosine monophosphate
  • G protein
  • Gastrin-releasing peptide
  • Growth factor
  • Phospholipase C

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Cholera toxin inhibits signal transduction by several mitogens and the in vitro growth of human small-cell lung cancer. / Viallet, J.; Sharoni, Y.; Frucht, H.; Jensen, R. T.; Minna, J. D.; Sausville, E. A.

In: Journal of Clinical Investigation, Vol. 86, No. 6, 12.1990, p. 1904-1912.

Research output: Contribution to journalArticle

Viallet, J. ; Sharoni, Y. ; Frucht, H. ; Jensen, R. T. ; Minna, J. D. ; Sausville, E. A. / Cholera toxin inhibits signal transduction by several mitogens and the in vitro growth of human small-cell lung cancer. In: Journal of Clinical Investigation. 1990 ; Vol. 86, No. 6. pp. 1904-1912.
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abstract = "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.",
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N2 - 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.

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