The PPAR-gamma modulator troglitazone sensitizes human malignant glioma cells to the death ligand TRAIL

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Induction of apoptosis by the death ligand TRAIL might be a promising therapeutic approach for malignant glioma. Since not all glioma cells are sensitive to TRAIL, there is a need to develop strategies to overcome TRAIL resistance in these tumors. Nuclear receptor PPAR gamma modulators have been described to alter apoptosis sensitivity in various tumor types, and, therefore, we examined whether a family of PPAR gamma-modulating drugs, the glitazones (troglitazone, ciglitazone, and pioglitazone), have the capability to sensitize human glioma cells to TRAIL-induced apoptosis. Glioma cell death caused by troglitazone was not dependent on caspase activation and did not result in cleavage of caspase 8. To test whether troglitazone can sensitize glioma cells to TRAIL, we treated a TRAIL-resistant subline of the human malignant glioma cell line T98G with a combination of troglitazone and TRAIL. Troglitazone co-treatment resulted in a prominent sensitization of glioma cells to TRAIL-induced apoptosis. This was accompanied by a marked increase of active caspase 8 (p18) as compared to treatment with TRAIL only. Moreover, troglitazone induced a strong reduction in protein expression levels of the FLICE-inhibitory protein (FLIP), but not of other anti-apoptotic proteins. This reduction of FLIP expression was observed only on protein but not mRNA level, indicating that troglitazone promoted FLIP protein degradation or, alternatively, inhibited FLIP protein synthesis. Interestingly, combined treatment of T98G cells with TRAIL and other glitazones (ciglitazone, pioglitazone) did not result in comparable sensitizing effects. We conclude that a combined treatment with troglitazone and TRAIL should be further evaluated as a promising experimental therapy for malignant glioma, especially since the glitazones are already clinically used as anti-diabetic drugs.