Cox-2-derived PGE2 induces Id1-dependent radiation resistance and self-renewal in experimental glioblastoma Journal Article
| Authors: | Cook, P. J.; Thomas, R.; Kingsley, P. J.; Shimizu, F.; Montrose, D. C.; Marnett, L. J.; Tabar, V. S.; Dannenberg, A. J.; Benezra, R. |
| Article Title: | Cox-2-derived PGE2 induces Id1-dependent radiation resistance and self-renewal in experimental glioblastoma |
| Abstract: | 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. © 2016 The Author(s) 2016. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. |
| Keywords: | glioblastoma; cox-2; radioresistance; id1; pge2 |
| Journal Title: | Neuro-Oncology |
| Volume: | 18 |
| Issue: | 10 |
| ISSN: | 1522-8517 |
| Publisher: | Oxford University Press |
| Date Published: | 2016-10-01 |
| Start Page: | 1379 |
| End Page: | 1389 |
| Language: | English |
| DOI: | 10.1093/neuonc/now049 |
| PROVIDER: | scopus |
| PMCID: | PMC5035519 |
| PUBMED: | 27022132 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 2 November 2016 -- Source: Scopus |
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