Peroxisome proliferator-activated receptors (PPAR) are novel nuclear receptors and PPARgamma ligands have been shown to produce pro-apoptotic effects in many cancer cell types, including colon cancer. PPARgamma ligands exert their effect through PPARgamma-dependent (genomic) and PPARgamma-independent (non-genomic) mechanisms. Recent evidence suggests that PPARgamma ligands exert their pro-apoptotic effects in part by directly antagonizing the NF-kappabeta pathway as well as through activation of the MAP kinase pathway. In this report, we have demonstrated that ciglitazone, a member of the thiazoldinedione class of PPARgamma ligands induces HT-29 colon cancer cells to undergo apoptosis and prior to apoptosis, ciglitazone exposure results in a transient phosphorylation of PPARgamma. This phosphorylation of PPARgamma was mediated through the ciglitazone-induced activation of Erk1/2. PPARgamma phosphorylation affected the genomic pathway by being inhibitory to PPARgamma-DNA binding and PPRE transcriptional activity, as well as the non-genomic pathway by increasing the physical interaction of PPARgamma with p65, leading to the inhibition of NF-kappabeta. Ciglitazone induced phosphorylation of PPARgamma through the MAP kinase pathway provides a potential regulatory mechanism for PPARgamma's physical interaction with p65, leading to inhibition of NF-kappabeta and subsequent apoptosis.

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Central effects of melatonin on the sympatho-adrenomedullary outflow were investigated in urethane-anesthetized rats. In the intact animals, intracerebroventricularly (i.c.v.) administered interleukin-1beta (IL-1beta) (100 ng/animal) slightly, but significantly, elevated the plasma level of noradrenaline (NA), but not the level of adrenaline (Ad). Melatonin (100 microg/animal, i.c.v.) did not modulate the effects of IL-1beta on plasma levels of catecholamines. In the pinealectomized animals, however, the same dose of IL-1beta markedly elevated plasma levels of both Ad and NA, and the elevation of Ad was more potent than that of NA. In these pinealectomized animals, the serum level of melatonin was significantly lower than that in the sham-operated control animals. Furthermore, the IL-1beta-induced elevations of plasma catecholamines in these pinealectomized animals were attenuated by i.c.v. administered melatonin. These results suggest that melatonin plays an inhibitory role in the central regulation of sympatho-adrenomedullary outflow in rats.

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