Cox-2-derived PGE2 induces Id1-dependent radiation resistance and self-renewal in experimental glioblastoma.

Cook PJ, Thomas R, Kingsley PJ, Shimizu F, Montrose DC, Marnett LJ, Tabar VS, Dannenberg AJ, Benezra R
Neuro Oncol. 2016 18 (10): 1379-89

PMID: 27022132 · PMCID: PMC5035519 · DOI:10.1093/neuonc/now049

BACKGROUND - In glioblastoma (GBM), Id1 serves as a functional marker for self-renewing cancer stem-like cells. We investigated the mechanism by which cyclooxygenase-2 (Cox-2)-derived prostaglandin E2 (PGE2) induces Id1 and increases GBM self-renewal and radiation resistance.

METHODS - Mouse and human GBM cells were stimulated with dimethyl-PGE2 (dmPGE2), a stabilized form of PGE2, to test for Id1 induction. To elucidate the signal transduction pathway governing the increase in Id1, a combination of short interfering RNA knockdown and small molecule inhibitors and activators of PGE2 signaling were used. Western blotting, quantitative real-time (qRT)-PCR, and chromatin immunoprecipitation assays were employed. Sphere formation and radiation resistance were measured in cultured primary cells. Immunohistochemical analyses were carried out to evaluate the Cox-2-Id1 axis in experimental GBM.

RESULTS - In GBM cells, dmPGE2 stimulates the EP4 receptor leading to activation of ERK1/2 MAPK. This leads, in turn, to upregulation of the early growth response1 (Egr1) transcription factor and enhanced Id1 expression. Activation of this pathway increases self-renewal capacity and resistance to radiation-induced DNA damage, which are dependent on Id1.

CONCLUSIONS - In GBM, Cox-2-derived PGE2 induces Id1 via EP4-dependent activation of MAPK signaling and the Egr1 transcription factor. PGE2-mediated induction of Id1 is required for optimal tumor cell self-renewal and radiation resistance. Collectively, these findings identify Id1 as a key mediator of PGE2-dependent modulation of radiation response and lend insight into the mechanisms underlying radiation resistance in GBM patients.

© The Author(s) 2016. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

MeSH Terms (16)

Animals Blotting, Western Brain Neoplasms Chromatin Immunoprecipitation Cyclooxygenase 2 Dinoprostone Enzyme-Linked Immunosorbent Assay Gene Knockdown Techniques Glioblastoma Humans Immunohistochemistry Inhibitor of Differentiation Protein 1 Mice Radiation Tolerance Real-Time Polymerase Chain Reaction Signal Transduction

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