title: The peroxisome proliferator-activated receptor-gamma agonist troglitazone inhibits transforming growth factor-beta-mediated glioma cell migration and brain invasion.
abstract: Gliomas are the most common primary tumors of the central nervous system, with glioblastomas as the most malignant entity. Rapid proliferation and diffuse brain invasion of these tumors are likely to determine the unfavorable prognosis. Considering its promigratory properties, the transforming growth factor-beta (TGF-beta) signaling pathway has become a major therapeutic target. Analyses of resected glioma tissues revealed an intriguing correlation between tumor grade and the expression of TGF-beta(1-3) as well as their receptors I and II. Here, we analyzed the effects of peroxisome proliferator-activated receptor gamma (PPAR-gamma) agonists on glioma proliferation, migration, and brain invasion. Using an organotypic glioma invasion model, we show that micromolar doses of the PPAR-gamma activator troglitazone blocked glioma progression without neurotoxic damage to the organotypic neuronal environment observed. This intriguing antiglioma property of troglitazone seems to be only partially based on its moderate cytostatic effects. We identified troglitazone as a potent inhibitor of glioma cell migration and brain invasion, which occurred in a PPAR-gamma-independent manner. The antimigratory property of troglitazone was in concordance with the transcriptional repression of TGF-beta(1-3) and their receptors I and II and associated with reduced TGF-beta release. Due to its capacity to counteract TGF-beta release and glioma cell motility and invasiveness already at low micromolar doses, troglitazone represents a promising drug for adjuvant therapy of glioma and other highly migratory tumor entities.
authors.affiliation: Department of NeuropathologyI, University of Erlangen, Erlangen, Germany, Germany.
authors.forename: Roland
authors.initials: R
authors.lastname: Coras
authors.forename: Annett
authors.initials: A
authors.lastname: Hölsken
authors.forename: Sebastian
authors.initials: S
authors.lastname: Seufert
authors.forename: Jan
authors.initials: J
authors.lastname: Hauke
authors.forename: Ilker Y
authors.initials: IY
authors.lastname: Eyüpoglu
authors.forename: Martin
authors.initials: M
authors.lastname: Reichel
authors.forename: Christian
authors.initials: C
authors.lastname: Tränkle
authors.forename: Florian A
authors.initials: FA
authors.lastname: Siebzehnrübl
authors.forename: Rolf
authors.initials: R
authors.lastname: Buslei
authors.forename: Ingmar
authors.initials: I
authors.lastname: Blümcke
authors.forename: Eric
authors.initials: E
authors.lastname: Hahnen
mesh_terms: D000818:Animals; D001483:Base Sequence; D001932:Brain Neoplasms / Q000473:pathology*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology*; D002839:Chromans / Q000494:pharmacology*; D017931:DNA Primers; D015536:Down-Regulation / Q000187:drug effects; D016193:G1 Phase / Q000187:drug effects; D005910:Glioma / Q000473:pathology*; D051379:Mice; D009361:Neoplasm Invasiveness; D047495:PPAR gamma / Q000819:agonists*; D045162:Thiazolidinediones / Q000494:pharmacology*; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000502:physiology; D000077288:Troglitazone
chemical_list: D002839:Chromans; D017931:DNA Primers; D047495:PPAR gamma; D045162:Thiazolidinediones; D016212:Transforming Growth Factor beta; D000077288:Troglitazone