Interaction of retinoic acid and interferon in renal cancer cell lines

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