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Reciprocal Regulation of SOCS 1 and SOCS3 Enhances Resistance to Ionizing Radiation in Glioblastoma Multiforme

Authors' Affiliations: Departments of ¹ Radiation Oncology, ² Urology and Human Genetics, ³ Pathology and Laboratory Medicine, and ⁴ Microbiology, Immunology, and Molecular Genetics, University of California at Los Angeles School of Medicine, Los Angeles, California and ⁵ Department of Molecular and Cellular Immunology, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan

Requests for reprints: Nicholas A. Cacalano, Department of Radiation Oncology, Center for Health Sciences, University of California at Los Angeles, Room B3-170, Los Angeles, CA 90095. Phone: 310-267-2803; Fax: 310-206-1260; E-mail: ncacalano{at}mednet.ucla.edu.

Purpose: The expression of suppressors of cytokine signaling 1 (SOCS1) and SOCS3 genes is dysregulated in several solid tumors, causing aberrant activation of cell growth and survival signaling pathways. In this study, we analyzed SOCS1 and SOCS3 gene expression in glioblastoma multiforme (GBM) and studied the role of each protein in GBM cell signaling and radiation resistance.

Experimental Design: SOCS1 and SOCS3 gene expression was analyzed in 10 GBM cell lines by reverse transcription-PCR and Western blotting. SOCS3 expression was also studied in 12 primary GBM tissues by immunohistochemistry. The methylation status of the SOCS1 and SOCS3 loci was determined by methylation-specific PCR. Extracellular signal-regulated kinase (ERK)-mitogen-activated protein kinase (MAPK) activation in GBM cell lines overexpressing SOCS1 or lacking SOCS3 was determined by phosphorylated-specific Western blotting. Radiation responses in SOCS1-positive and SOCS3-deficient GBM cell lines and fibroblasts from wild-type and SOCS1 or SOCS3 knockout mice were studied in a clonogenic survival assay.

Results: All GBM cell lines tested lacked SOCS1 expression, whereas GBM cell lines and primary GBM tumor samples constitutively expressed SOCS3. SOCS1 gene repression was linked to hypermethylation of the SOCS1 genetic locus in GBM cells. Reintroduction of SOCS1 or blocking SOCS3 expression sensitized cells to radiation and decreased the levels of activated ERK MAPKs in GBM cells.

Conclusions: SOCS1 and SOCS3 are aberrantly expressed in GBM cell lines and primary tissues. Altered SOCS gene expression leads to increased cell signaling through the ERK-MAPK pathway and may play a role in disease pathogenesis by enhancing GBM radioresistance.

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