Journal Article

RBIO-02. CALPASTATIN PHOSPHORYLATION REGULATES RADIATION RESPONSE IN GLIOBLASTOMA

Emily Bassett, Kamalakannan Palanichamy, Mitchell Pearson, S Jaharul Haque and Arnab Chakravarti

in Neuro-Oncology

Volume 19, issue suppl_6, pages vi217-vi218
Published in print November 2017 | ISSN: 1522-8517
Published online November 2017 | e-ISSN: 1523-5866 | DOI: https://dx.doi.org/10.1093/neuonc/nox168.880

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Abstract

Glioblastoma (GBM) is an aggressive, malignant brain tumor that often develops resistance to conventional chemotherapy and radiation treatments. In order to identify signaling pathways involved in the development of radiation resistance, we performed mass spectrometry-based phospho-proteomic profiling of 5 GBM cell lines and normal human astrocytes before and after radiation treatment. Fold changes in phosphorylation were calculated for each peptide across all cell lines at 30 seconds and 4 hours post-radiation. We found that radiation induces phosphorylation of calpastatin, an endogenous inhibitor of calpain proteases, specifically in GBM stem cells (GSCs). Radiation-induced phosphorylation of calpastatin at a serine within the inhibitory domain was validated by western blot with a phospho-specific antibody. In order to test the functional significance of phosphorylated calpastatin, we utilized site-directed mutagenesis to generate non-phosphorylatable and phospho-mimetic calpastatin mutants. Western blot analyses of GBM cell lines stably expressing the calpastatin mutant proteins show that calpastatin phosphorylation leads to increased calpain activity following radiation treatment. Our results indicate that calpastatin phosphorylation promotes radiation resistance in GBM by increasing the activity of calpain proteases, which are known to promote survival and invasion in cancers.

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Subjects: Medical Oncology ; Neurology