title: Induction of apoptosis in human and rat glioma by agonists of the nuclear receptor PPARgamma.
abstract: Malignant astrocytomas are among the most common brain tumours and few therapeutic options exist. It has recently been recognized that the ligand-activated nuclear receptor PPARgamma can regulate cellular proliferation and induce apoptosis in different malignant cells. We report the effect of three structurally different PPARgamma agonists inducing apoptosis in human (U87MG and A172) and rat (C6) glioma cells. The PPARgamma agonists ciglitazone, LY171 833 and prostaglandin-J2, but not the PPARalpha agonist WY14643, inhibited proliferation and induced cell death. PPARgamma agonist-induced cell death was characterized by DNA fragmentation and nuclear condensation, as well as inhibited by the synthetic receptor-antagonist bisphenol A diglycidyl ether (BADGE). In contrast, primary murine astrocytes were not affected by PPARgamma agonist treatment. The apoptotic death in the glioma cell lines treated with PPARgamma agonists was correlated with the transient up-regulation of Bax and Bad protein levels. Furthermore, inhibition of Bax expression by specific antisense oligonucleotides protected glioma cells against PPARgamma-mediated apoptosis, indicating an essential role of Bax in PPARgamma-induced apoptosis. However, PPARgamma agonists not only induced apoptosis but also caused redifferentiation as indicated by outgrowth of long processes and expression of the redifferentiation marker N-cadherin in response to PPARgamma agonists. Taken together, treatment of glioma cells with PPARgamma agonists may hold therapeutic potential for the treatment of gliomas.
authors.affiliation: Department of Neurology, University Bonn, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Zander
authors.forename: Jürgen A
authors.initials: JA
authors.lastname: Kraus
authors.forename: Christian
authors.initials: C
authors.lastname: Grommes
authors.forename: Uwe
authors.initials: U
authors.lastname: Schlegel
authors.forename: Douglas
authors.initials: D
authors.lastname: Feinstein
authors.forename: Thomas
authors.initials: T
authors.lastname: Klockgether
authors.forename: Gary
authors.initials: G
authors.lastname: Landreth
authors.forename: Jessica
authors.initials: J
authors.lastname: Koenigsknecht
authors.forename: Michael T
authors.initials: MT
authors.lastname: Heneka
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015820:Cadherins / Q000096:biosynthesis; D002352:Carrier Proteins / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D053938:DNA Fragmentation / Q000187:drug effects; D004353:Drug Evaluation, Preclinical; D005910:Glioma / Q000188:drug therapy* / Q000378:metabolism*; D006801:Humans; D009687:Nuclear Proteins / Q000819:agonists* / Q000378:metabolism; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D015230:Prostaglandin D2 / Q000031:analogs & derivatives* / Q000494:pharmacology; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2; D011743:Pyrimidines / Q000494:pharmacology; D051381:Rats; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists* / Q000378:metabolism; D013844:Thiazoles / Q000494:pharmacology; D045162:Thiazolidinediones; D014157:Transcription Factors / Q000819:agonists* / Q000378:metabolism; D014407:Tumor Cells, Cultured; D051028:bcl-2-Associated X Protein; D051025:bcl-Associated Death Protein
chemical_list: C494819:BAD protein, human; C494826:BAX protein, human; C494821:Bad protein, rat; C494828:Bax protein, rat; D015820:Cadherins; D002352:Carrier Proteins; D009687:Nuclear Proteins; D016376:Oligonucleotides, Antisense; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D011743:Pyrimidines; D018160:Receptors, Cytoplasmic and Nuclear; D013844:Thiazoles; D045162:Thiazolidinediones; D014157:Transcription Factors; D051028:bcl-2-Associated X Protein; D051025:bcl-Associated Death Protein; C037112:9-deoxy-delta-9-prostaglandin D2; C006253:pirinixic acid; D015230:Prostaglandin D2; C039671:ciglitazone