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

Peter J. Cook, Rozario Thomas, Philip J. Kingsley, Fumiko Shimizu, David C. Montrose, Lawrence J. Marnett, Viviane S. Tabar, Andrew J. Dannenberg, Robert Benezra

Research output: Contribution to journalArticlepeer-review

38 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1379-1389
Number of pages11
JournalNeuro-oncology
Volume18
Issue number10
DOIs
StatePublished - Oct 1 2016

Keywords

  • Cox-2
  • Id1
  • PGE2
  • glioblastoma
  • radioresistance

ASJC Scopus subject areas

  • Oncology
  • Clinical Neurology
  • Cancer Research

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