The role of peroxisome proliferator-activated receptor-β/δ in epithelial cell growth and differentiation

Burdick, Andrew D.; Kim, Dae Joon; Peraza, Marjorie A.; Gonzalez, Frank J.; Peters, Jeffrey M.

doi:10.1016/j.cellsig.2005.07.009

Cited by 142 publications

(148 citation statements)

References 89 publications

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“…Recent literatures suggest that PPAR-b activation induces the terminal differentiation of keratinocytes, coupled with the inhibition of cell proliferation (Schmuth et al, 2004;Kim et al, 2006;Burdick et al, 2006). These studies enable us to hypothesize that PPAR-b possibly has some role in the differentiation of colon cancer, and might affect the cell adhesion, migration and/or invasion that are associated with tumor differentiation.…”

Section: Introductionmentioning

confidence: 87%

Knockdown of peroxisome proliferator-activated receptor-β induces less differentiation and enhances cell–fibronectin adhesion of colon cancer cells

et al. 2009

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The role of peroxisome proliferator-activated receptor-b/ d (PPAR-b/d) in the pathogenesis of colon cancer remains highly controversial. This study specifically silenced the PPAR-b expression in three colon cancer cell lines with different metastatic potentials. Although PPAR-b knockdown resulted in more malignant morphological changes, bigger colony sizes and lower carcinoembryonic antigen (CEA) secretion, and enhanced the cell-fibronectin adhesion, cell invasion and migration were unaffected. These effects were stronger in poorly metastatic cell lines compared with highly metastatic ones. Simultaneously, PPAR-b knockdown decreased the mRNAs encoding adipocyte differentiation-related protein and liver fatty acid binding protein, and increased the mRNA of ILK, whereas the mRNAs encoding integrin-b1 and angiopoietin-like 4 were unchanged. Using immunohistochemistry, we determined that the intensity of PPAR-b expression was stronger in rectal cancers with better differentiation than in those with poor differentiation, and was stronger in early-stage tumors than in advanced ones. Together, these findings consistently indicate that PPAR-b may facilitate differentiation and inhibit the cell-fibronectin adhesion of colon cancer, having a role as an inhibitor in the carcinogenesis and progression of colorectal cancer. Interestingly, PPAR-b seems to have a more important role in poorly metastatic cells than in highly metastatic ones.

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Section: Introductionmentioning

confidence: 87%

Knockdown of peroxisome proliferator-activated receptor-β induces less differentiation and enhances cell–fibronectin adhesion of colon cancer cells

et al. 2009

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“…Purebred wild-type and PPARβ-null mice on a SV/129 background were used and have been previously described [22,23]. Primary hepatocytes were isolated from two male wildtype mice (10 day old) and two male PPARβ-null mice (5 day old).…”

Section: Isolation Maintenance and Infection Of Primary Hepatocytesmentioning

confidence: 99%

“…Of the three PPAR genes (α, β/δ, γ), the PPARβ/δ isoform is the least well-studied in terms of its biological functions and endogenous ligands. PPARβ/δ plays an important role in differentiation of epithelial tissues, fatty acid catabolism in skeletal muscle, improvement of insulin sensitivity, attenuated weight gain and elevated HDL levels [10]. Emerging evidence suggests the presence of this receptor is important in ameliorating the effects of hepatotoxicants.…”

Section: Introductionmentioning

confidence: 99%

The oxidative stress mediator 4-hydroxynonenal is an intracellular agonist of the nuclear receptor peroxisome proliferator-activated receptor-β/δ (PPARβ/δ)

Coleman

Prabhu

Thompson

et al. 2007

Free Radical Biology and Medicine

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104

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Liver insufficiency and damage is a major cause of death and disease worldwide and may result from exposure to environmental toxicants, specific combinations or dosages of pharmaceuticals and microbial metabolites. The generation of reactive intermediates, in particular 4-hydroxynonenal (4-HNE), is a common event in liver damage caused by a variety of hepatotoxic drugs and solvents. The peroxisome proliferator-activated receptors (PPARs) are nuclear receptors that are involved in the transcriptional regulation of lipid metabolism as well as other biological functions. Importantly, we have observed that the PPARβ/δ −/− mouse is more susceptible to chemically-induced hepatotoxicity than its wildtype counterpart, and our objective in this study was to elucidate the mechanism(s) by which PPARβ/δ confers protection to hepatocytes. We hypothesized that PPARβ/ δ plays a protective role by responding to toxic lipids and altering gene expression accordingly. In support, oxidized-VLDL and constituents including 13-S-hydroxyoctadeca-dienoic acid (13(S)-HODE) and 4-HNE are PPARβ/δ ligands. A structure-activity relationship was established where 4-HNE and 4-hydroperoxynonenal (4-HpNE) enhanced the activity of the PPARβ/δ subtype while 4-hyroxy-hexenal (4-HHE), 4-oxo-2-Nonenal (4-ONE), and trans-4,5-epoxy-2(E)-decenal did not activate this receptor. Increasing PPARβ/δ activity with a synthetic agonist decreased sensitivity of hepatocytes to 4-HNE and other toxic agents, whereas inhibition of this receptor had the opposite result. Gene expression microarray analysis identified several important PPARβ/δ-regulated detoxification enzymes involved in 4-HNE metabolism that are regulated at the transcript level. This research established 4-HNE as an endogenous modulator of PPARβ/δ activity and raises the possibility that agonists of this nuclear receptor may be utilized to prevent or treat liver disease associated with oxidative damage.

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“…This concern is due in large part to the effects of PPARβ/δ and its ligands on cell growth and carcinogenesis. Indeed, some reports suggest that ligand activation of PPARβ/δ potentiates cell growth, while other reports suggest that ligand activation of PPARβ/δ attenuates cell growth (reviewed in [3]). For example, culturing human breast and prostate cancer cell lines in the presence of a PPARβ/δ ligand causes an increase in cell proliferation [14].…”

Section: Introductionmentioning

confidence: 99%

“…In the past decade, the functional role(s) of PPARs have been delineated and range from modulation of glucose and lipid homeostasis to regulation of cell growth and differentiation (reviewed in [1][2][3][4][5]). There is great potential for agonists of PPARβ/δ for the treatment and prevention of a number of diseases.…”

Section: Introductionmentioning

confidence: 99%

Ligand activation of peroxisome proliferator-activated receptor-β/δ(PPARβ/δ) inhibits cell growth of human N/TERT-1 keratinocytes

Burdick¹,

Bility

Girroir³

et al. 2007

Cellular Signalling

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The functional role of peroxisome proliferator-activated receptor-β (PPARβ; also referred to as PPARδ) in epidermal cell growth remains controversial. Recent evidence suggests that ligand activation of PPARβ/δ increases cell growth and inhibits apoptosis in epidermal cells. In contrast, other reports suggest that ligand activation of PPARβ/δ leads to the induction of terminal differentiation and inhibition of cell growth. In the present study, the effect of the highly specific PPARβ/δ ligand GW0742 on cell growth was examined using a human keratinocyte cell line (N/ TERT-1) and mouse primary keratinocytes. Ligand activation of PPARβ/δ with GW0742 prevented cell cycle progression from G1 to S phase and attenuated cell proliferation in N/TERT-1 cells. Despite specifically activating PPARβ/δ as revealed by target gene induction, no changes in PTEN, PDK and ILK expression or downstream phosphorylation of Akt were found in either N/TERT-1 cells or primary keratinocytes. Further, altered cell growth resulting from serum withdrawal and the induction of caspase-3 activity by ultraviolet radiation were unchanged in the absence of PPARβ/δ expression and/or the presence of GW0742. While no changes in the expression of mRNAs encoding cell cycle control proteins were found in response to GW0742, a significant decrease in the level of ERK phosphorylation was observed. Results from these studies demonstrate that ligand activation of PPARβ/δ does not lead to an anti-apoptotic effect in either human or mouse keratinocytes, but rather, leads to inhibition of cell growth likely through the induction of terminal differentiation.

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The role of peroxisome proliferator-activated receptor-β/δ in epithelial cell growth and differentiation

Cited by 142 publications

References 89 publications

Knockdown of peroxisome proliferator-activated receptor-β induces less differentiation and enhances cell–fibronectin adhesion of colon cancer cells

Knockdown of peroxisome proliferator-activated receptor-β induces less differentiation and enhances cell–fibronectin adhesion of colon cancer cells

The oxidative stress mediator 4-hydroxynonenal is an intracellular agonist of the nuclear receptor peroxisome proliferator-activated receptor-β/δ (PPARβ/δ)

Ligand activation of peroxisome proliferator-activated receptor-β/δ(PPARβ/δ) inhibits cell growth of human N/TERT-1 keratinocytes

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