Abstract 2888: SOCS3-deficient cells are defective in the DNA damage response

Abstract

Abstract The SOCS family of proteins are negative feedback inhibitors of cytokine and growth factor signal transduction, targeting primarily the STAT family of transcription factors. Several SOCS genes, including SOCS1 and SOCS3 are hypermethylated and silenced in solid tumors, which is believed to impart a growth advantage via hyperactivation of the STAT pathway. Despite the growing role of SOCS in the pathogenesis of cancer, very little is known of their role in modulating tumor cell responses to therapy. We recently identified an unexpected function for SOCS3 in the context of the DNA damage response. We found that cells lacking SOCS3 are sensitive to ionizing radiation (IR) in a clonogenic survival assay due to impaired p21 (Cip1/Waf-1) upregulation, which results in failure of the radiation-induced G1-S checkpoint. Normal cell cycle arrest and p21 upregulation could be restored in SOCS3-/- MEFs by overexpression of a phosphorylation-deficient, dominant-negative (DN) mutant of STAT3. Two STAT3-dependent genes known to suppress p21 expression, c-Myc and BCL6 are overrepresented in SOCS3-deficient MEFs. Likewise, human tumor cells that repress SOCS3 expression by epigenetic silencing are also more radiosensitive than their SOCS3+ counterparts. In agreemwnt with our data in MEFs, c-Myc and BCL6 are overexpressed in human tumor cells that silence SOCS3 expression by promoter hypermethulation, suggesting that tumors lacking SOCS3 may be more vulnerable to IR-based therapies due to impaired cell cycle arrest and DNA repair. Our data suggest that therapeutic targeting of SOCS3 in tumor cells could sensitize cells to IR and improve the effectiveness of radiotherapy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2888. doi:10.1158/1538-7445.AM2011-2888