Interaction of Retinoic Acid and Interferon in Renal Cancer Cell Lines

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Abstract
Retinoic acid (RA) can potentiate the antitumor effect of interferons (IFN) in a variety of tumor types, including renal cell carcinoma (RCC). The mechanisms by which RA and IFN increase the antitumor effects in RCC are unknown. We used growth assays and mobility shift assays to examine the effects of combining 13-cis-retinoic acid (CRA) and IFN-α (plus IFN-γ) on proliferation and on the expression of the IFN-specific transcription factor IFN-stimulated gene factor 3 (ISGF3) in RCC cell lines. Combining CRA and IFN-α resulted in a significant increase in growth inhibition in four cell lines compared with IFN-α or CRA alone. Binding of nuclear extracts from RCC cells to an IFN-stimulated response element (ISRE) oligonucleotide probe following incubation with IFN-α was not increased by CRA but was significantly increased by pretreatment by IFN-γ in a time-dependent fashion. Proliferation assays showed that sequential addition of IFNγ and IFN-α significantly increased growth inhibition. IFN-α but not IFN-γ or CRA increased the cellular levels Stat2 and p48 but not Stat1. IFN-γ pretreatment enhanced the upregulation of p48 levels by IFN-α. Combining RA and IFN results in additive growth inhibition on RCC cell lines. This increase in growth inhibition is not mediated by increased ISGF3 expression.