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Description:
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The gamma isoform of peroxisome -proliferator activated receptor (PPAR -gamma ) is a member of the super family of nuclear hormone receptors and shows much promise as a chemopreventative and therapeutic target for colorectal cancer . Activation of PPAR -gamma by thiazolidinediones (TZDs ) inhibits proliferation and induces differentiation in human colon cancer cells . RS5444 , a novel TZD , is a high affinity and high specificity ligand for PPAR -gamma . We have shown that RS5444 markedly reduced the proliferation of MOSER S human colorectal cancer cells under anchorage dependent and independent conditions . The inhibitory effect of RS5444 was irreversible . RS5444 also significantly repressed the invasive phenotype , but not motility , of these tumor cells .
Towards elucidating the activated PPAR -gamma controlled genomic program responsible for these observed phenotypes , functional genomic analysis was performed using a two -class longitudinal microarray data set in the presence and absence of RS5444 . Differential expression of genes was obtained using an empirical Bayesian modification to the multivariate HotellingT2 score . We have demonstrated this statistical machine learning technique to be superior in controlling type II error in our dataset than more commonly used algorithms for two -class analysis . Likewise , through the use of several bioinformatics techniques , including frequency -based pathway analysis , and functional ontology analysis , we found a yet unappreciated tumor -suppressing network involving a feedback mechanism between PPAR -gamma , DSCR1 and calcineurin -mediated signaling of NFATc in colorectal cancer cells . To this end , we have demonstrated a direct connection between NFATc and DSCR1 in MOSER S colorectal cancer cells . Likewise , we have demonstrated a correlation between the sensitivity of PPAR -gamma in other colorectal cancer cells , and the messenger abundance of DSCR1 . Finally , we have demonstrated that knockdown of DSCR1 messenger obviates the phenotypic effects of activated PPAR -gamma in vitro .
To our knowledge these data represent , for the first time , a network between PPAR -gamma , DSCR1 , and NFATc signaling in the context of tumor -suppressor activity . This preliminary evidence is consistent with our working hypothesis that an oncology patients receptiveness to TZD treatment may be largely dependent on the specific tumors endogenous abundance of DSCR1 . We believe without a critical endogenous level of DSCR1 , activated PPARγ may revert to a tumor -activator instead of a tumor -suppressor . |