PPAR? agonists inhibit cell growth and suppress the expression of cyclin D1 and EGF-like growth factors in ras-transformed rat intestinal epithelial cells

Kitamura, Shinji; Miyazaki, Yoshiji; Hiraoka, Shintaro; Nagasawa, Yutaka; Toyota, Miyuki; Takakura, Rena; Kiyohara, Tatsuya; Shinomura, Yasuhisa; Matsuzawa, Yūji

doi:10.1002/ijc.1470

Cited by 45 publications

(27 citation statements)

References 39 publications

(39 reference statements)

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“…According to previous observation in the HL-60 cell model, cyclin D1 expression was not affected by PPAR ligand treatment, in contrast to that observed in pancreatic (Toyota et al, 2002) and in ras-transformed rat intestinal epithelial cells (Kitamura et al, 2001). In cell culture D-type cyclins, which show tissue specific expression, do not seem to functionally overlap (Sherr, 1995).…”

Section: Ppar Ligand Effects On Growth-related Gene Expression 935mentioning

confidence: 59%

Peroxisome Proliferator-Activated Receptor Ligands Affect Growth-Related Gene Expression in Human Leukemic Cells

Laurora¹,

Pizzimenti²,

Briatore³

et al. 2003

J Pharmacol Exp Ther

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Peroxisome proliferator-activated receptors (PPARs) are ligandactivated nuclear receptors. Three subtypes of PPARs (␣, ␤, and ␥) have been identified in different tissues. PPAR␣ and PPAR␥ ligands inhibit cell proliferation and induce differentiation in several human cell models. We demonstrated that both PPAR␣ (clofibrate and ciprofibrate) and PPAR␥ ligands (troglitazone and 15 deoxyprostaglandin J2, 15d-PGJ2) inhibited growth, induced the onset of monocytic-like differentiation, and increased the proportion of G 0 /G 1 cells in the HL-60 leukemic cell line. Moreover, 3 days after the treatment with 2.5 M 15d-PGJ2, an increase in sub-G 0 /G 1 population occurred, compatible with an induction of programmed cell death. To clarify the mechanisms involved in HL-60 growth inhibition due to the effects of PPAR ligands, we investigated their action on the expression of some genes involved in the control of cell proliferation, differentiation, and cell cycle progression such as c-myc, c-myb, and cyclin D1 and D2. Clofibrate (50 M), ciprofibrate (50 M), and 15d-PGJ2 (2.5 M) inhibited c-myb and cyclin D2 expression, whereas they did not affect c-myc and cyclin D1 expression. Only troglitazone (5 M) decreased c-myc mRNA and protein levels, besides decreasing c-myb and cyclin D2. The down-regulations of c-myb and cyclin D2 expression represent the first evidence of the inhibitory effect exerted by PPAR ligands on these genes. Moreover, the inhibition of c-myc expression by troglitazone may depend on a PPAR-independent mechanism.

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Section: Ppar Ligand Effects On Growth-related Gene Expression 935mentioning

confidence: 59%

Peroxisome Proliferator-Activated Receptor Ligands Affect Growth-Related Gene Expression in Human Leukemic Cells

Laurora¹,

Pizzimenti²,

Briatore³

et al. 2003

J Pharmacol Exp Ther

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“…Moreover, pioglitazone, a PPAR␥ agonist, has been shown to abrogate left ventricular remodeling and myocyte hypertrophy following experimental myocardial infarction (53). Interestingly, ligand activation of PPAR␥ inhibits HBEGF promoter activity in rat intestinal cells, possibly by suppressing the transcriptional activities of AP-1 and Ets (54). PPAR␥ ligands also reduce levels and activities of various metalloproteinases including metalloproteinases 1, 2, 3, 7, 9, and 13 (53,(55)(56)(57)(58)(59)(60)(61).…”

Section: Discussionmentioning

confidence: 99%

Role of the Epidermal Growth Factor Receptor in Signaling Strain-dependent Activation of the Brain Natriuretic Peptide Gene

Anderson¹,

Wang²,

Gardner

2004

Journal of Biological Chemistry

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The epidermal growth factor receptor (EGFR) and ectoshedding of heparin-binding epidermal growth factor (HBEGF), an EGFR ligand, have been linked to the development of cardiac myocyte hypertrophy. However, the precise role that the liganded EGFR plays in the transcriptional activation of the gene program that accompanies hypertrophy remains undefined. Utilizing the human (h) BNP gene as a model of hypertrophy-dependent gene activation, we show that activation of the EGFR plays an important role in mediating mechanical strain-dependent stimulation of the hBNP promoter. Strain promotes endothelin (ET) generation through NAD(P)H oxidase-dependent production of reactive oxygen species. ET in turn induces metalloproteinase-mediated cleavage of pro-HBEGF and ectoshedding of HBEGF, which activates the EGFR and stimulates hBNP promoter activity. HBEGF also stimulates other phenotypic markers of hypertrophy including protein synthesis and sarcomeric assembly. The antioxidant N-acetylcysteine or the NAD(P)H oxidase inhibitor, apocynin, inhibited strain-dependent activation of the ET-1 promoter, HBEGF shedding, and hBNP promoter activation. The metalloproteinase inhibitor, GM-6001, prevented the induction of HBEGF ectoshedding and the hBNP promoter response to strain, suggesting a critical role for the metalloproteinase-dependent cleavage event in signaling the strain response. These findings suggest that metalloproteinase activity as an essential step in this pathway may prove to be a relevant therapeutic target in the management of cardiac hypertrophy.

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“…Activation of cyclin D1 in response to the mitogenic signals leads to G1/S progression and increased proliferation. PPARγ activation in intestinal epithelial cells results in the inhibition of cell cycle and S-phase entry through a decrease in cyclin D1 expression [51,52] . In colon cancer cells, PPARγ ligand treatment not only decreases the protein level of cyclin D1, but also increases the cyclin-dependent kinase (CDK) inhibitors p21 CIP1 and p27 KIP1 through both increased transcriptional activity and inhibition of proteasome degradation [53][54][55] .…”

Section: Inhibition Of Cellular Proliferationmentioning

confidence: 99%

Peroxisome proliferator-activated receptor γ and colorectal cancer

Dai

Wang²

2010

WJGO

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Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear hormone receptor superfamily and ligand-activated transcription factors. PPARγ plays an important role in adipocyte differentiation, lipid storage and energy dissipation in adipose tissue, and is involved in the control of inflammatory reactions as well as in glucose metabolism through the improvement of insulin sensitivity. Growing evidence has demonstrated that activation of PPARγ has an antineoplastic effect in tumors, including colorectal cancer. High expression of PPARγ is detected in human colon cancer cell lines and adenocarcinoma. This review describes the molecular mechanisms by which PPARγ regulates tumorigenesis in colorectal cancer, and examines current clinical trials evaluating PPARγ agonists as therapeutic agents for colorectal cancer.

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PPAR? agonists inhibit cell growth and suppress the expression of cyclin D1 and EGF-like growth factors in ras-transformed rat intestinal epithelial cells

Cited by 45 publications

References 39 publications

Peroxisome Proliferator-Activated Receptor Ligands Affect Growth-Related Gene Expression in Human Leukemic Cells

Peroxisome Proliferator-Activated Receptor Ligands Affect Growth-Related Gene Expression in Human Leukemic Cells

Role of the Epidermal Growth Factor Receptor in Signaling Strain-dependent Activation of the Brain Natriuretic Peptide Gene

Peroxisome proliferator-activated receptor γ and colorectal cancer

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