Enhancement by Retinoic Acid and Dibutyryl Cyclic Adenosine 3′:5′-Monophosphate of the Differentiation and Gene Expression of Human Neuroblastoma Cells Induced by Interferon

Takakazu Higuchi, Gregory E. Hannigan, David Malkin, Herman Yeger, Bryan R.G. Williams

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Human neuroblastoma cell lines are induced to differentiate and display neuronal phenotypes when treated with interferon (IFN)-a2, retinoic acid (RA), or dibutyryl cyclic AMP (dbcAMP). We investigated the effects of combinations of these agents in induction-differentiation in the neuroblastoma cell line, NUB-6. The inductive effect of IFN-αwas markedly enhanced when used in combination with RA or dbcAMP. In parallel, RA or dbcAMP also enhanced the level of 2′-5′-oligoadenylate (2–5A) synthetase, an enzyme induced by IFNs and implicated in their biological action. The levels of another IFN-inducible enzyme, p68 kinase, were not enhanced by the combination treatments. The enhancement effects appeared to be exerted largely at the posttranscriptional level as both RA and dbcAMP stabilized IFN-induced 2–5A synthetase mRNA, resulting in increased enzyme activity. Thus, the 2–5A synthetase system is likely involved in mediating the IFN-α-induced differentiation of neuroblastoma cells and may also mediate the enhancement effects of RA and dbcAMP on IFN activity in these cells. These results also provide a rational basis for establishing a combination therapeutic approach for the treatment of neuroblastoma.

Original languageEnglish
Pages (from-to)3958-3964
Number of pages7
JournalCancer Research
Issue number15
Publication statusPublished - 1 Aug 1991
Externally publishedYes

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