Curcumin interrupts the interaction between the androgen receptor and Wnt/ß-catenin signaling pathway in LNCaP prostate cancer cells.

Recently, studies have investigated the significance of the Wnt/ß-catenin pathway in prostate cancer. The transcriptional activity of the androgen receptor (AR) is modulated by interaction with coregulators, one of which is ß-catenin. Curcumin, a dietary yellow pigment of Curcuma longa, has emerged as having a chemopreventive role. Although curcumin has been shown to inhibit AR expression, its molecular mechanism has not been fully elucidated. In this study, whether curcumin mediates the Wnt/ß-catenin signaling pathway with regard to AR/ß-catenin interactions was studied. Curcumin was shown to induce significant inhibition of AR expression in a dose-dependent manner. Marked curcumin-induced suppression of ß-catenin was shown in the nuclear and cytoplasmic extracts as well as whole cell lysates. Further analysis revealed that phosphorylation of Akt and glycogen synthase kinase-3ß were attenuated, but phosphorylated ß-catenin was increased after curcumin treatment. Finally, cyclin D1 and c-myc, the target gene of the ß-catenin/T-cell factor transcriptional complex, were also decreased. These findings suggest that curcumin modulates the Wnt/ß-catenin signaling pathway and might have a significant role in mediating inhibitory effects on LNCaP prostate cancer cells.

Fine mapping of QTL for prepulse inhibition in LG/J and SM/J mice using F(2) and advanced intercross lines.

Prepulse inhibition (PPI) of the startle response is a measure of sensorimotor gating, a process that filters out extraneous sensory, motor and cognitive information. Humans with neurological and psychiatric disorders, including schizophrenia, obsessive-compulsive disorder and Huntington's disease, exhibit a reduction in PPI. Habituation of the startle response is also disrupted in schizophrenic patients. In order to elucidate the genes involved in sensorimotor gating, we phenotyped 472 mice from an F(2) cross between LG/J × SM/J for PPI and genotyped these mice genome-wide using 162 single nucleotide polymorphism (SNP) markers. We used prepulse intensity levels that were 3, 6 and 12 dB above background (PPI3, PPI6 and PPI12, respectively). We identified a significant quantitative trait locus (QTL) on chromosome 12 for all three prepulse intensities as well as a significant QTL for both PPI6 and PPI12 on chromosome 11. We identified QTLs on chromosomes 7 and 17 for the startle response when sex was included as an interactive covariate and found a QTL for habituation of the startle response on chromosome 4. We also phenotyped 135 mice from an F(34) advanced intercross line (AIL) between LG/J × SM/J for PPI and genotyped them at more than 3000 SNP markers. Inclusions of data from the AIL mice reduced the size of several of these QTLs to less than 5 cM. These results will be useful for identifying genes that influence sensorimotor gaiting and show the power of AIL for fine mapping of QTLs.