RS5444, a novel PPARγ agonist, regulates aspects of the differentiated phenotype in nontransformed intestinal epithelial cells

Chen, Lu; Bush, Craig R.; Necela, Brian M.; Wei-dong, SU; Yanagisawa, Masahiro; Anastasiadis, Panos Z.; Fields, Alan P.; Thompson, E. Aubrey

doi:10.1016/j.mce.2006.02.006

Cited by 28 publications

(64 citation statements)

References 49 publications

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“…RS5444 is a high affinity PPAR␥ agonist that has been shown to regulate growth and motility of intestinal epithelial as well as thyroid cancer cells (14,52,53). Rosiglitazone (49653, Invitrogen) was purchased from ChemPacific.…”

Section: Methodsmentioning

confidence: 99%

“…Microarray Preparation, Quality Control, Preprocessing of Probe Level Data, and Analysis of Differential ExpressionmRNA from technical replicates in the presence or absence of RS5444 at 6-h intervals (0, 6, 12, 18, and 24 h) was isolated as described above. Gene profiling analysis was performed using HG133 version 2 Gene Chip Microarrays (Affymetrix) as described previously (14). Affymetrix.CEL files, extracted from Affymetrix GCOS software, were loaded into the R language environment (version 2.2.1) with the Bioconductor (68) libraries (version 1.7) and run under the Linux distribution OpenSuse, version 10, 64-bit operating system with 10 gigabytes of available memory.…”

Section: Methodsmentioning

confidence: 99%

“…MOSER cells express PPAR␣, -␦, and -␥ isoforms (56, 78), but we have previously shown that RS5444 activates PPAR␥ but does not activate PPAR␣ or PPAR␦ (14). MOSER cells were cultured in the presence of RS5444 for 24 h. RNA was isolated every 2 h after treatment, and protein was isolated every 12 h after treatment.…”

Section: Moser Cells As a Model For Suppression Of Early Events Inmentioning

confidence: 99%

“…PPAR␥2 is abundant in adipocytes (9, 10), whereas PPAR␥1 is more widely distributed in the body, with the highest levels of expression reported in adipocytes and colonic epithelium (8,11,12). PPAR␥ plays an important role in adipocyte differentiation (9,13) and controls important differentiated functions in intestinal epithelial cells (14). However, the physiological role of PPAR␥ in the colon is largely unknown or has been inferred from studies with transformed colonic epithelial cells.…”

mentioning

confidence: 99%

“…Because PPAR␥ is a transcription factor, it is likely that the tumor-suppressive effects of this receptor are because of changes in gene expression and that the mechanism of action of PPAR␥ might be inferred from a functional genomic study of the effects of thiazolidinediones on early stage colon cancer cells. The observations described below result from such a study in which we used the high affinity PPAR␥ agonist RS5444 (14,(51)(52)(53) to activate PPAR␥ in MOSER cells. These cells have sustained an APC loss-of-function mutation followed by loss of heterozygosity of the wildtype APC allele; however, MOSER cells retain TGF␤ sensitivity (54,55) and have wild-type K-Ras, indicating that they represent a late adenoma or early adenocarcinoma stage.…”

mentioning

confidence: 99%

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Functional Genomic Analysis Reveals Cross-talk between Peroxisome Proliferator-activated Receptor γ and Calcium Signaling in Human Colorectal Cancer Cells

Bush

Havens

Necela

et al. 2007

Journal of Biological Chemistry

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Activation of PPAR␥ in MOSER cells inhibits anchoragedependent and anchorage-independent growth and invasion through Matrigel-coated transwell membranes. We carried out a longitudinal two-class microarray analysis in which mRNA abundance was measured as a function of time in cells treated with a thiazolidinedione PPAR␥ agonist or vehicle. A statistical machine learning algorithm that employs an empirical Bayesian implementation of the multivariate HotellingT2 score was used to identify differentially regulated genes. HotellingT2 scores, MB statistics, and maximum median differences were used as figures of merit to interrogate genomic ontology of these targets. Three major cohorts of genes were regulated: those involved in metabolism, DNA replication, and migration/motility, reflecting the cellular phenotype that attends activation of PPAR␥. The bioinformatic analysis also inferred that PPAR␥ regulates calcium signaling. This response was unanticipated, because calcium signaling has not previously been associated with PPAR␥ activation. Ingenuity pathway analysis inferred that the nodal point in this cross-talk was Down syndrome critical region 1 (DSCR1). DSCR1 is an endogenous calcineurin inhibitor that blocks dephosphorylation and activation of members of the cytoplasmic component of nuclear factor of activated T cells transcription factors. Lentiviral short hairpin RNA-mediated knockdown of DSCR1 blocks PPAR␥ inhibition of proliferation and invasion, indicating that DSCR1 is required for suppression of transformed properties of early stage colorectal cancer cells by PPAR␥. These data reveal a novel, heretofore unappreciated link between PPAR␥ and calcium signaling and indicate that DSCR1, which has previously been thought to function by suppression of the angiogenic response in endothelial cells, may also play a direct role in transformation of epithelial cells.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Moser Cells As a Model For Suppression Of Early Events Inmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Functional Genomic Analysis Reveals Cross-talk between Peroxisome Proliferator-activated Receptor γ and Calcium Signaling in Human Colorectal Cancer Cells

Bush

Havens

Necela

et al. 2007

Journal of Biological Chemistry

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The high affinity peroxisome proliferator‐activated receptor‐gamma agonist RS5444 inhibits both initiation and progression of colon tumors in azoxymethane‐treated mice

Wei-dong

Necela

Fujiwara

et al. 2008

Intl Journal of Cancer

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We evaluated RS5444, a thiazolidinedione high affinity PPARγ agonist, for the ability to inhibit colon carcinogenesis in azoxymethane (AOM)-treated mice. In our initial experiment, mice were treated with RS5444 during AOM treatment, and the drug was withdrawn 12 weeks after the last injection of AOM. RS5444 significantly inhibited aberrant crypt focus formation under these circumstances. Furthermore, exposure to RS5444 during the course of AOM treatment effectively blocked colon tumor formation after withdrawal of the agonist. PPARγ expression and nuclear localization were reduced in adenomas. RS5444 did not inhibit DNA synthesis in tumor cells, suggesting that PPARγ activity was impaired in adenomas. To test this hypothesis, pre-existing adenomas were treated with RS5444 for 16 weeks. We observed a slight, albeit not statistically significant, reduction in tumor incidence in RS5444-treated mice. However, histological examination revealed that tumors from RS5444-treated mice were of significantly lower grade, as evaluated by the extent of dysplasia. Furthermore, carcinoma in situ was observed in about one-third of control tumors, but was never observed in RS5444-treated tumors. We conclude that RS5444 inhibits both initiation and progression of colon tumors in the AOM model of sporadic colon carcinogenesis.

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Tissue Distribution and Versatile Functions of PPARs

Youssef

Badr

2013

Peroxisome Proliferator-Activated Receptors

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RS5444, a novel PPARγ agonist, regulates aspects of the differentiated phenotype in nontransformed intestinal epithelial cells

Cited by 28 publications

References 49 publications

Functional Genomic Analysis Reveals Cross-talk between Peroxisome Proliferator-activated Receptor γ and Calcium Signaling in Human Colorectal Cancer Cells

Functional Genomic Analysis Reveals Cross-talk between Peroxisome Proliferator-activated Receptor γ and Calcium Signaling in Human Colorectal Cancer Cells

The high affinity peroxisome proliferator‐activated receptor‐gamma agonist RS5444 inhibits both initiation and progression of colon tumors in azoxymethane‐treated mice

Tissue Distribution and Versatile Functions of PPARs

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