Aberrant regulation of SOCS1 and SOCS3 enhances resistance to ionizing radiation in glioblastoma multiforme.

5172 Glioblastoma multiforme (GBM) is a malignant cancer of the brain which is highly resistant to radiation therapy. Significant effort has been made to identify signaling mechanisms that can be exploited to increase the effectiveness of radiation therapy and improve patient outcome. In this study, we have determined that two members of the Suppressors of Cytokine Signaling (SOCS) family of proteins, SOCS1 and SOCS3 are dysregulated in GBM. SOCS3 is constitutively expressed in both GBM cell lines and primary GBM tumor tissues by a STAT3-dependent mechanism, and SOCS1 expression is repressed epigenetically by CpG island methylation of the SOCS1 locus. Blocking SOCS3 expression, or overexpression of SOCS1 suppresses ERK MAP kinase activation and increases the sensitivity of GBM cells to ionizing radiation. Our results suggest that reciprocal regulation of SOCS1 and SOCS3 contributes to the acquisition of radioresistance in GBM, perhaps by increasing the levels of activated MAP kinases. SOCS1 and SOCS3 may be important biomarkers of aggressive, radioresistant cancers, and therapeutics which modulate SOCS expression or function may therefore be useful to lower the threshold of GBM cells to radiation-induced cell death and improve the outcome of standard anti-cancer therapies.