Peter J Cook1, Rozario Thomas1, Philip J Kingsley1, Fumiko Shimizu1, David C Montrose1, Lawrence J Marnett1, Viviane S Tabar1, Andrew J Dannenberg1, Robert Benezra2. 1. Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, New York (P.J.C., R.T., R.B.); Department of Molecular Biology, Weill Cornell Graduate School of Medical Sciences of Cornell University, New York, New York (R.T.); Departments of Biochemistry, Chemistry, and Pharmacology, A.B. Hancock Jr. Memorial Laboratory for Cancer Research, Vanderbilt Institute of Chemical Biology, Vanderbilt University School of Medicine, Nashville, Tennessee (P.J.K., L.J.M.); Department of Neurosurgery, Memorial Sloan Kettering Cancer Center, New York, New York (F.S., V.S.T); Department of Medicine, Weill Cornell Medical College, New York, (D.C.M, A.J.D.). 2. Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, New York (P.J.C., R.T., R.B.); Department of Molecular Biology, Weill Cornell Graduate School of Medical Sciences of Cornell University, New York, New York (R.T.); Departments of Biochemistry, Chemistry, and Pharmacology, A.B. Hancock Jr. Memorial Laboratory for Cancer Research, Vanderbilt Institute of Chemical Biology, Vanderbilt University School of Medicine, Nashville, Tennessee (P.J.K., L.J.M.); Department of Neurosurgery, Memorial Sloan Kettering Cancer Center, New York, New York (F.S., V.S.T); Department of Medicine, Weill Cornell Medical College, New York, (D.C.M, A.J.D.) r-benezra@ski.mskcc.org ajdannen@med.cornell.edu.
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.
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 ERK1/2MAPK. 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.
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