title: Cox-2-derived PGE2 induces Id1-dependent radiation resistance and self-renewal in experimental glioblastoma.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
authors.affiliation: 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.).
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Cook
authors.affiliation: 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.).
authors.forename: Rozario
authors.initials: R
authors.lastname: Thomas
authors.affiliation: 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.).
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Kingsley
authors.affiliation: 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.).
authors.forename: Fumiko
authors.initials: F
authors.lastname: Shimizu
authors.affiliation: 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.).
authors.forename: David C
authors.initials: DC
authors.lastname: Montrose
authors.affiliation: 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.).
authors.forename: Lawrence J
authors.initials: LJ
authors.lastname: Marnett
authors.affiliation: 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.).
authors.forename: Viviane S
authors.initials: VS
authors.lastname: Tabar
authors.affiliation: 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.).
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Dannenberg
authors.affiliation: 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.
authors.forename: Robert
authors.initials: R
authors.lastname: Benezra
mesh_terms: D000818:Animals; D015153:Blotting, Western; D001932:Brain Neoplasms / Q000378:metabolism / Q000473:pathology*; D047369:Chromatin Immunoprecipitation; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D015232:Dinoprostone / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D055785:Gene Knockdown Techniques; D005909:Glioblastoma / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D007150:Immunohistochemistry; D051798:Inhibitor of Differentiation Protein 1 / Q000378:metabolism*; D051379:Mice; D011836:Radiation Tolerance / Q000502:physiology*; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology
chemical_list: D051798:Inhibitor of Differentiation Protein 1; D051546:Cyclooxygenase 2; D015232:Dinoprostone
keywords: Cox-2; Id1; PGE2; glioblastoma; radioresistance