title: The PPARgamma ligands PGJ2 and rosiglitazone show a differential ability to inhibit proliferation and to induce apoptosis and differentiation of human glioblastoma cell lines.
abstract: Peroxisome proliferator-activated receptor gamma (PPARgamma) is involved in the control of cell proliferation, apoptosis and differentiation in various tumor cells. Among PPARgamma ligands, 15-deoxy-Delta12,14-prostaglandin J2 (PGJ2), the ultimate metabolite of PGD2, plays a role in the biology of brain tumors. It is still unclear to which extent the anti-proliferative and differentiation-promoting activity of PGJ2 is mediated through PPARgamma. We compared the effects of PGJ2 with those of rosiglitazone - the synthetic agonist with the highest affinity for PPARgamma - in 4 human glioblastoma cell lines (A172, U87-MG, M059K, M059J). All cell lines expressed high levels of PPARgamma, consistent with the high levels of PPARgamma protein in 5 tumor samples. Both PGJ2 and rosiglitazone inhibited proliferation of all cell lines with a G2/M arrest and apoptosis, but only PGJ2 up-regulated p21Cip/WAF1. The growth inhibitory effect was partially reversed by the PPARgamma antagonist GW9662. We studied the time sequence of selected molecular events, that lead glioblastoma cells to apoptosis and/or differentiation, after treatment with both agonists. M059K cells committed to undergo apoptosis by PGJ2, initially up-regulated PPARgamma, and then down-regulated PPARgamma as they began apoptosis. Apoptotic cells also increased their expression of retinoic acid receptor beta (RARbeta) and retinoid X receptor alpha (RXRalpha). PGJ2 increased expression of glial fibrillary acidic protein (GFAP) and decreased levels of vimentin, structural proteins modulated during astrocytic differentiation. Unexpectedly, PGJ2 up-regulated the expression of cyclooxygenase-2 (COX-2). Rosiglitazone caused the same pattern of PPARgamma, RARbeta and RXRalpha expression as PGJ2, but no significant modulation of p21Cip/WAF1, cytoskeletal proteins or COX-2 occurred. Our data indicate that PGJ2, and rosiglitazone suppress cell proliferation and cause apoptosis in glioblastoma cell lines, most likely through a PPARgamma-dependent pathway. By contrast, the modulation of differentiation-associated proteins by PGJ2, but not rosiglitazone, suggests that PGJ2 promotes differentiation of glioblastoma cells independently of PPARgamma activation.
authors.affiliation: Division of Pediatric Oncology, Catholic University of Rome, 00168 Rome, Italy. rmorosetti@rm.unicatt.it
authors.forename: Roberta
authors.initials: R
authors.lastname: Morosetti
authors.forename: Tiziana
authors.initials: T
authors.lastname: Servidei
authors.forename: Massimiliano
authors.initials: M
authors.lastname: Mirabella
authors.forename: Sergio
authors.initials: S
authors.lastname: Rutella
authors.forename: Annunziato
authors.initials: A
authors.lastname: Mangiola
authors.forename: Giulio
authors.initials: G
authors.lastname: Maira
authors.forename: Renato
authors.initials: R
authors.lastname: Mastrangelo
authors.forename: H Phillip
authors.initials: HP
authors.lastname: Koeffler
mesh_terms: D017209:Apoptosis; D002454:Cell Differentiation / Q000187:drug effects; D002467:Cell Nucleus / Q000276:immunology; D049109:Cell Proliferation / Q000187:drug effects; D051546:Cyclooxygenase 2; D016195:G2 Phase / Q000187:drug effects; D015870:Gene Expression / Q000187:drug effects; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D005909:Glioblastoma / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D008565:Membrane Proteins; D016900:Neurofilament Proteins / Q000378:metabolism; D047495:PPAR gamma / Q000819:agonists* / Q000032:analysis / Q000037:antagonists & inhibitors; D015230:Prostaglandin D2 / Q000031:analogs & derivatives* / Q000494:pharmacology*; D011451:Prostaglandin-Endoperoxide Synthases / Q000235:genetics / Q000378:metabolism; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D015854:Up-Regulation; D014746:Vimentin / Q000378:metabolism
chemical_list: D005904:Glial Fibrillary Acidic Protein; D007527:Isoenzymes; D008565:Membrane Proteins; D016900:Neurofilament Proteins; D047495:PPAR gamma; D045162:Thiazolidinediones; D014746:Vimentin; C066858:neurofilament protein NF 68; D000077154:Rosiglitazone; C037112:9-deoxy-delta-9-prostaglandin D2; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D015230:Prostaglandin D2