TY - JOUR T1 - Regulation of Interferon-inducible Proteins by Doxorubicin via IFNγ-JAK-STAT Signaling in Tumor Cells JF - Molecular Pharmacology JO - Mol Pharmacol DO - 10.1124/mol.111.075994 SP - mol.111.075994 AU - Janine Hussner AU - Sabine Ameling AU - Elke Hammer AU - Susann Herzog AU - Leif Steil AU - Matthias Schwebe AU - Juliane Niessen AU - Henry WS Schroeder AU - Heyo K Kroemer AU - Christoph A Ritter AU - Uwe Volker AU - Sandra Bien Y1 - 2012/01/01 UR - http://molpharm.aspetjournals.org/content/early/2012/02/09/mol.111.075994.abstract N2 - Activation of the immune system is a way for host tissue to defend itself against tumor growth. Hence, treatment strategies that are based on immunomodulation are on the rise. Conventional cytostatic drugs such as the anthracycline doxorubicin can also activate immune cell functions of macrophages and natural killer cells. In addition, cytotoxicity of doxorubicin can be enhanced by combining this drug with the cytokine IFNγ. Although doxorubicin is one of the most applied cytostatics, the molecular mechanisms of its immunomodulation ability are not investigated thoroughly. In microarray analyses of HeLa cells, a set of 19 genes related to interferon signaling was significantly overrepresented among genes regulated by doxorubicin exposure including STAT-1, -2, IRF9, NMI, and caspase 1. Regulation of these genes by doxorubicin was verified with Real-Time PCR and immunoblotting. An enhanced secretion of IFNγ was observed when HeLa cells were exposed to doxorubicin as compared to untreated cells. IFNγ neutralizing antibodies and inhibition of JAK-STAT signaling (ATA, AG490, STAT1 siRNA) significantly abolished doxorubicin-stimulated expression of interferon signaling-related genes. Furthermore, inhibition of JAK-STAT signaling significantly reduced doxorubicin induced caspase 3 activation and desensitized HeLa cells to doxorubicin cytotoxicity. In conclusion, we demonstrate that doxorubicin induces interferon-responsive genes via IFNγ-JAK-STAT1 signaling and that this pathway is relevant for doxorubicin's cytotoxicity in HeLa cells. As immunomodulation is a promising strategy in anticancer treatment, this novel mode of action of doxorubicin may help to further improve the use of this drug among different types of anticancer treatment strategies. ER -