Cox-2-derived PGE2 induces Id1-dependent radiation resistance and self-renewal in experimental glioblastoma
Cox-2-derived PGE2 induces Id1-dependent radiation resistance and self-renewal in experimental glioblastoma
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DOI：
10.1093/neuonc/now049
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发表时间：
2016-10-01
期刊：
影响因子：
15.9
通讯作者：
Benezra, Robert
中科院分区：
文献类型：
--
作者：
Cook, Peter J.;Thomas, Rozario;Benezra, Robert
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 E-2 (PGE(2)) induces Id1 and increases GBM self-renewal and radiation resistance.Mouse and human GBM cells were stimulated with dimethyl-PGE(2) (dmPGE(2)), a stabilized form of PGE(2), 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 PGE(2) 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.In GBM cells, dmPGE(2) 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.In GBM, Cox-2-derived PGE(2) induces Id1 via EP4-dependent activation of MAPK signaling and the Egr1 transcription factor. PGE(2)-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 PGE(2)-dependent modulation of radiation response and lend insight into the mechanisms underlying radiation resistance in GBM patients.
