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Research Articles: Therapeutics, Targets, and Development

The peroxisome proliferator-activated receptor- agonist troglitazone inhibits transforming growth factor-ß–mediated glioma cell migration and brain invasion

Departments of ¹ Neuropathology, ² Neurosurgery, and ³ Experimental Medicine II, University of Erlangen, Erlangen, Germany; ⁴ Institute of Human Genetics, Institute of Genetics, and Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany; and ⁵ Department of Pharmacology and Toxicology, Institute of Pharmacy, University of Bonn, Bonn, Germany

Requests for reprints: Eric Hahnen, Institute of Human Genetics, University of Cologne, Kerpenerstr. 34, 50931 Cologne, Germany. Phone: 49-221-478-86464; Fax: 49-221-478-86465. E-mail: eric.hahnen{at}uk-koeln.de

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-ß (TGF-ß) 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-ß_1-3 as well as their receptors I and II. Here, we analyzed the effects of peroxisome proliferator-activated receptor (PPAR-) agonists on glioma proliferation, migration, and brain invasion. Using an organotypic glioma invasion model, we show that micromolar doses of the PPAR- 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-–independent manner. The antimigratory property of troglitazone was in concordance with the transcriptional repression of TGF-ß_1-3 and their receptors I and II and associated with reduced TGF-ß release. Due to its capacity to counteract TGF-ß 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. [Mol Cancer Ther 2007;6(6):1745–54]

Grant support: Nolting Stiftung (University of Cologne; E. Hahnen), the ELAN-Fonds (University of Erlangen-Nuremberg), and the Wilhelm Sander-Stiftung (WSS 2005.089.1; I.Y. Eyüpoglu and I. Blümcke).

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Received 12/11/06; revised 3/27/07; accepted 5/ 1/07.