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.