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Apoptosis

, Volume 11, Issue 9, pp 1503–1512 | Cite as

Troglitazone sensitizes tumor cells to TRAIL-induced apoptosis via down-regulation of FLIP and Survivin

  • Kerstin Schultze
  • Barbara Böck
  • Anika Eckert
  • Lena Oevermann
  • Dirk Ramacher
  • Otmar Wiestler
  • Wilfried RothEmail author
Article

Abstract

Induction of apoptosis by the death ligand TRAIL might be a promising therapeutic approach in cancer therapy. However, since not all tumor cells are sensitive to TRAIL, there is a need for the development of strategies to overcome TRAIL-resistance. The results of the present study show that the anti-diabetic drug troglitazone sensitizes human glioma and neuroblastoma cells to TRAIL-induced apoptosis. This process is accompanied by a substantial increase of active caspase 8 and active caspase 3, but it is independent of troglitazone's effects on the nuclear receptor PPAR-γ. Troglitazone induces a pronounced reduction in protein expression levels of the anti-apoptotic FLICE-inhibitory protein (FLIP) without affecting FLIP mRNA levels. Further, protein and mRNA expression levels of the anti-apoptotic protein Survivin significantly decrease upon treatment with troglitazone. Moreover, sensitization to TRAIL is partly accompanied by an up-regulation of the TRAIL receptor, TRAIL-R2. A combined treatment with troglitazone and TRAIL might be a promising experimental therapy because troglitazone sensitizes tumor cells to TRAIL-induced apoptosis via various mechanisms, thereby minimizing the risk of acquired tumor cell resistance.

Keywords

Apoptosis Brain tumors Troglitazone FLIP Survivin 

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Copyright information

© Springer Science + Business Media, LLC 2006

Authors and Affiliations

  • Kerstin Schultze
    • 1
  • Barbara Böck
    • 1
  • Anika Eckert
    • 1
  • Lena Oevermann
    • 1
  • Dirk Ramacher
    • 1
  • Otmar Wiestler
    • 1
  • Wilfried Roth
    • 1
    Email author
  1. 1.Molecular Neuro-OncologyGerman Cancer Research Center (DKFZ)HeidelbergGermany

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