Journal Article

Tetradecylthioacetic acid inhibits growth of rat glioma cells <i>ex vivo</i> and <i>in vivo</i> via PPAR-dependent and PPAR-independent pathways

Kjetil Berge, Karl J. Tronstad, Esben N. Flindt, Thomas H. Rasmussen, Lise Madsen, Karsten Kristiansen and Rolf K. Berge

in Carcinogenesis

Volume 22, issue 11, pages 1747-1755
Published in print November 2001 | ISSN: 0143-3334
Published online November 2001 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/22.11.1747
Tetradecylthioacetic acid inhibits growth of rat glioma cells ex vivo and in vivo via PPAR-dependent and PPAR-independent pathways

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The peroxisome proliferator-activated receptors (PPARs) are transcription factors involved in fatty acid metabolism and energy homeostasis. The PPARs also play crucial roles in the control of cellular growth and differentiation. Especially, the recently emerged concept of ligand-dependent PPARγ-mediated inhibition of cancer cell proliferation through induction of G1-phase arrest and differentiation is of clinical interest to cancer therapy. Tetradecylthioacetic acid (TTA) is a sulphur-substituted saturated fatty acid analog with unique biochemical properties. In this study, we investigated the effects of TTA-administration on cell proliferation in glioma cancer models. The rat glioma cell line BT4Cn, whether grown in culture or implanted in rats, expressed significant levels of PPARγ and PPARδ, with PPARγ being the predominant PPAR subtype. In BT4Cn cells, TTA activated all PPAR subtypes in a dose-dependent manner. In cell culture experiments, the PPARγ-selective ligand BRL49653 moderately inhibited growth of BT4Cn cells, whereas administration of TTA resulted in a marked growth inhibition. Administration of the PPARγ-selective antagonist GW9662 abolished BRL49653-induced growth inhibition, but only marginally reduced the effect of TTA. TTA reduced tumor growth and increased the survival time of rats with implanted BT4Cn tumor. TTA-induced apoptosis in BT4Cn cells, and the administration of TTA led to cytochrome c release from mitochondria and increased the glutathione content in glioma cells. In conclusion, our results indicate that TTA inhibits proliferation of glioma cancer cells through both PPARγ-dependent and PPARγ-independent pathways, of which the latter appears to predominate.

Keywords: ANT, adenine nucleotide translocase; ΔΨ, mitochondrial membrane potential; NHR, nuclear hormone receptor; PPAR, peroxisome proliferator-activated receptor; PPRE, peroxisome proliferator response element; PTP, permeability transition pore; RXR, retinoid-x receptor; TTA, tetradecylthioacetic acid

Journal Article.  6787 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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