Abstract
The growth-inhibitory effect of human immune interferon (IFN-γ) was investigated in human colon carcinoma cell line HT-29. Three-day treatment of HT-29 cells with IFN-γ (10 to 200 units/ml) resulted in 30 to 90% growth inhibition and 40 to 99% reduction in colony formation. Measurement of DNA, RNA, and protein synthesis following IFN-γ treatment showed a dose-dependent reduction in all 3 parameters. The associated changes in (2′,5′)oligoadenylate [(2′,5′)oligo(A)] pathway were measured under growth-inhibitory conditions. Upon 1-day exposure to 25 to 200 units/ml of IFN-γ, (2′,5′)oligo(A) synthetase activity was induced 10- to 15-fold and remained elevated for 3 days, whereas (2′,5′)oligo(A) phosphodiesterase activity remained unchanged. There was no detectable increase in intracellular (2′,5′)oligo(A) levels after IFN-γ treatment, and ribosomal RNA degradation was not observed. Accompanying 1-day treatment with IFN-γ (100 units/ml) was an induction of a polyamine-dependent protein kinase, which was double-stranded RNA-independent and phosphorylated endogenous polypeptides with molecular weights of 68,000 and 72,000. A similar exposure of cells to IFN-γ (25 to 100 units/ml) resulted in 30 to 70% inhibition of ornithine decarboxylase activity; however, no significant alteration in intracellular polyamine levels was observed. These data suggest that IFN-γ-dependent toxicity is not related to (2′,5′)oligo(A) activation of a latent endoribonuclease but is accompanied by protein phosphorylation, which is, in part, stimulated by exogenous polyamines.
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