RT Journal Article
SR Electronic
T1 Regulation of Interferon-inducible Proteins by Doxorubicin via IFNγ-JAK-STAT Signaling in Tumor Cells
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP mol.111.075994
DO 10.1124/mol.111.075994
A1 Janine Hussner
A1 Sabine Ameling
A1 Elke Hammer
A1 Susann Herzog
A1 Leif Steil
A1 Matthias Schwebe
A1 Juliane Niessen
A1 Henry WS Schroeder
A1 Heyo K Kroemer
A1 Christoph A Ritter
A1 Uwe Volker
A1 Sandra Bien
YR 2012
UL http://molpharm.aspetjournals.org/content/early/2012/02/09/mol.111.075994.abstract
AB 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.