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 f actors involved in fatty acid metabolism and energy homeostasis. The PPARs also play crucial roles in the control of cellular growth and differentiati on. Especially, the recently emerged concept of ligand-dependent PPAR gamma -mediated inhibition of cancer cell proliferation through induction of Gl- phase arrest and differentiation is of clinical interest to cancer therapy. Tetradecylthioacetic acid (TTA) is a sulphur-substituted saturated fatty a cid analog with unique biochemical properties. In this study, we investigat ed the effects of TTA-administration on cell proliferation in glioma cancer models. The rat glioma cell line BT4Cn, whether grown in culture or implan ted in rats, expressed significant levels of PPAR gamma and PPAR delta, wit h PPAR gamma being the predominant PPAR subtype. In BT4Cn cells, TTA activa ted all PPAR subtypes in a dose-dependent manner. In cell culture experimen ts, the PPAR gamma -selective ligand BRL49653 moderately inhibited growth o f BT4Cn cells, whereas administration of TTA resulted in a marked growth in hibition. Administration of the PPAR gamma -selective antagonist GW9662 abo lished 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 resu lts indicate that TTA inhibits proliferation of glioma cancer cells through both PPAR gamma -dependent and PPAR gamma -independent pathways, of which the latter appears to predominate.