MODULATION OF INTERFERON (IFN)-INDUCIBLE GENE-EXPRESSION BY RETINOIC ACID - UP-REGULATION OF STAT1 PROTEIN IN IFN-UNRESPONSIVE CELLS

Interferons (IFN) and retinoids failed to inhibit the growth of a numb er of breast tumor cell lines, However, a combination of these two bio logical response modifiers significantly suppressed the cell growth at pharmacologically achievable doses. The molecular basis for such enha ncement was investigated in MCF-7, a breast tumor cell line resistant to growth inhibition by IFN-beta. Pretrentment of cells with retinoic acid (RA) for 16 h followed by IFN-beta, but not the converse, induced cytotoxic effects in the cells. Continuous presence of RA was not nec essary, although it enhanced the degree of cell death when present. Fu rther analyses revealed that IFN-beta failed to activate IFN-stimulate d gene transcription. However, IFN-beta strongly up-regulated the gene expression in RA-pretreated cells. Both IFN-beta- and IFN-gamma-induc ible gene expression were enhanced via a modulation of the transcripti onal factor IFN-stimulated gene factors-3 and GAF binding to respectiv e cognate regulatory elements. STAT1 was undetectable in these cells p rior to RA treatment: RA increased the levels of this crucial regulato r, thereby restoring IFN responses. Thus, BA augmentation of STAT1 may be an early step in the cooperative anti-tumor effects of IFN and RA.