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Cox-2-derived PGE2 induces Id1-dependent radiation resistance and self-renewal in experimental glioblastoma
- Source :
- Neuro-oncology. 18(10)
- Publication Year :
- 2015
-
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.
- Subjects :
- 0301 basic medicine
MAPK/ERK pathway
Inhibitor of Differentiation Protein 1
Cancer Research
Small interfering RNA
Chromatin Immunoprecipitation
Blotting, Western
Enzyme-Linked Immunosorbent Assay
Real-Time Polymerase Chain Reaction
Radiation Tolerance
Dinoprostone
03 medical and health sciences
Mice
Downregulation and upregulation
Basic and Translational Investigation
Radioresistance
Animals
Humans
Transcription factor
Chemistry
Brain Neoplasms
Immunohistochemistry
Chromatin
030104 developmental biology
Oncology
Cyclooxygenase 2
Gene Knockdown Techniques
Cancer research
Neurology (clinical)
Signal transduction
Glioblastoma
Chromatin immunoprecipitation
Signal Transduction
Subjects
Details
- ISSN :
- 15235866
- Volume :
- 18
- Issue :
- 10
- Database :
- OpenAIRE
- Journal :
- Neuro-oncology
- Accession number :
- edsair.doi.dedup.....36ebcd12fc818fa9653dacfe123889b3