Interferon-alpha and transforming growth factor-beta co-induce growth inhibition of human tumor cells.
A hallmark of resistance to type I interferons (IFNs) is the lack of antiproliferative responses. We show here that costimulation with IFN-alpha and transforming growth factor beta-1 (TGF-beta) 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-alpha and TGF-beta, 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-beta activity. The antiproliferative activity of S100A2 is significantly enhanced by IFN-alpha in stably transfected ME15 or D10 cell lines. We show for the first time that IFN-alpha is a potent inducer of intracellular calcium release required for activation of S100A2. Our study provides a functional link between IFN-alpha and TGF-beta signaling and extends the function of IFN signaling to calcium-sensitive processes.
Foser
S
S
Roche Center for Medical Genomics, F. Hoffmann-La Roche AG, 4070, Basel, Switzerland.
Redwanz
I
I
Ebeling
M
M
Heizmann
C W
CW
Certa
U
U
D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002630:Chemotactic Factors / Q000502:physiology; D019008:Drug Resistance, Neoplasm; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects; D023281:Genomics; D006801:Humans; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000502:physiology; D016898:Interferon-alpha / Q000494:pharmacology*; D008545:Melanoma / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D009418:S100 Proteins / Q000502:physiology; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000494:pharmacology*
D000970:Antineoplastic Agents; D002630:Chemotactic Factors; D018972:Insulin-Like Growth Factor Binding Protein 3; D016898:Interferon-alpha; D009418:S100 Proteins; C098997:S100A2 protein, human; D016212:Transforming Growth Factor beta