Tetradecylthioacetic acid inhibits growth of rat glioma cells ex vivo and in vivo via PPAR-dependent and PPAR-independent pathways.
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 PPARgamma-mediated inhibition of cancer cell proliferation through induction of G(1)-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 PPARgamma and PPARdelta, with PPARgamma being the predominant PPAR subtype. In BT4Cn cells, TTA activated all PPAR subtypes in a dose-dependent manner. In cell culture experiments, the PPARgamma-selective ligand BRL49653 moderately inhibited growth of BT4Cn cells, whereas administration of TTA resulted in a marked growth inhibition. Administration of the PPARgamma-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 PPARgamma-dependent and PPARgamma-independent pathways, of which the latter appears to predominate.
Berge
K
K
Department of Clinical Biochemistry, Haukeland Hospital, University of Bergen, N-5021 Bergen, Norway. kjetil.berge@ikb.uib.no
Tronstad
K J
KJ
Flindt
E N
EN
Rasmussen
T H
TH
Madsen
L
L
Kristiansen
K
K
Berge
R K
RK
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D002455:Cell Division / Q000187:drug effects; D003574:Cytochrome c Group / Q000378:metabolism; D017931:DNA Primers / Q000737:chemistry; D015870:Gene Expression / Q000187:drug effects; D005910:Glioma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D005978:Glutathione / Q000378:metabolism; D066298:In Vitro Techniques; D008024:Ligands; D008297:Male; D008856:Microscopy, Fluorescence; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D010957:Plasmids; D051381:Rats; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013440:Sulfides / Q000494:pharmacology*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D014407:Tumor Cells, Cultured / Q000187:drug effects* / Q000502:physiology
D000975:Antioxidants; D003574:Cytochrome c Group; D017931:DNA Primers; D008024:Ligands; D018160:Receptors, Cytoplasmic and Nuclear; D013440:Sulfides; D014157:Transcription Factors; C062078:1-(carboxymethylthio)tetradecane; D005978:Glutathione