Interferon-alpha and transforming growth factor-β co-induce growth inhibition of human tumor cells

Abstract.

A hallmark of resistance to type I interferons (IFNs) is the lack of antiproliferative responses. We show here that costimulation with IFN-α and transforming growth factor beta-1 (TGF-β) potentiates antiproliferative activity in a sensitive (ME15) and resistant (D10) human melanoma cell line. A DNA microarray-based search for proliferation control genes involved that are cooperatively activated by IFN-α and TGF-β, yielded 28 genes. Among these are the insulin-like growth factor-binding protein 3 (IGFBP3) and the calcium-binding protein S100A2; we demonstrate, that recombinant IGFBP3 protein is a potent growth inhibitor requiring TGF-β activity. The antiproliferative activity of S100A2 is significantly enhanced by IFN-α in stably transfected ME15 or D10 cell lines. We show for the first time that IFN-α is a potent inducer of intracellular calcium release required for activation of S100A2. Our study provides a functional link between IFN-α and TGF-β signaling and extends the function of IFN signaling to calcium-sensitive processes.