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Chair(s): Robbins, Michael; Almasan, Alex
(PD001) Suppressors of Cytokine Signaling as Modulators of Radiation Response.
Sitko, John*,1, McBride, William1, 1 Radiation Oncology, Los Angeles, CA, USA
ABSTRACT- Suppressors of cytokine signaling (SOCS) proteins are cytokine and growth factor inducible regulators of signal transduction. SOCS expression is dysregulated in several types of tumors including colorectal neoplasia and non-small-cell lung cancer where the SOCS1 and SOCS3 promoters are hypermethalated, respectively. Although it has been shown that some SOCS family members are upregulated in response to ultraviolet radiation, we are unaware of any published data on the effects of ionizing radiation (IR) on members of the SOCS family or their possible role in modulating radiation responses. We present here data suggesting such a role for SOCS3. We have shown that radiation can induce SOCS3 expression at the mRNA level and also results in an increase in SOCS3 phosphorylation as assessed by Western blotting. Further, overexpression of SOCS3 in the human glioblastoma multiforme (GBM) cell line SF763 increased the survival fraction 3-10 fold after exposure to 10 Gy IR. Similar results were obtained with the 3T3 fibroblast cell line. Western blotting reveals a decrease in phosphorylated Akt and an increase in phosphorylated Erk in SF763 cells overexpressing SOCS3 compared to wild-type 6 hours after a 2 Gy IR dose. SOCS3 overexpression also affected cell cycle progression and this is currently being investigated within the context of radiation responses. Cancer-related changes in SOCS family members may therefore not only be important in defining tumor behavior but also in tumor radiation resistance and this pathway could serve as a target for manipulation to increase the therapeutic benefit of radiation therapy.
Key words: SOCS, GBM, AKT, Erk
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