Troglitazone induces apoptosis via the p53 and Gadd45 pathway in vascular smooth muscle cells

Okura, Takafumi; Nakamura, Michio; Takata, Yasunori; Watanabe, Sachiko; Kitami, Yutaka; Hiwada, Kunio

doi:10.1016/s0014-2999(00)00758-5

Cited by 104 publications

(78 citation statements)

References 39 publications

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“…The detailed analysis of the effects of ligands on the cells which do not express PPARg should provide important clues to understand this phenomenon. Okura et al (2000) demonstrated that troglitazone can induce vascular smooth muscle cell apoptosis via the tumour suppressor p53, but not by PPARg activation. We have previously shown by functional analysis of separated alleles in yeast (FASAY) assay that the p53-gene status of OUMS-27 is a mutant-type (Kunisada et al, 1998).…”

Section: Discussionmentioning

confidence: 99%

“…It has been shown that PPARg has regulatory functions in the cell cycle by altering cell growth (Motomura et al, 2000;Okura et al, 2000;Morrison and Farmer, 1999). Recently, Motomura et al (2000) reported that activation of PPARg by troglitazone inhibited cell growth and G1 arrest through the increase of cycline dependent kinase inhibitor p27 Kip1 in human pancreatic carcinoma cells.…”

Section: Discussionmentioning

confidence: 99%

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Inhibition of human chondrosarcoma cell growth via apoptosis by peroxisome proliferator-activated receptor-γ

et al. 2002

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A rare immunohistochemical study using 28 surgical sections of human chondrosarcoma revealed that 67.9% of tumour cells had weak (10-40%) or strong (440%) positive immunoreaction for peroxisome proliferator-activated receptor-g. The expression of peroxisome proliferator-activated receptor-g mRNA and protein in human chondrosarcoma cell line OUMS-27 was also determined by reverse transcription-polymerase chain reaction and immunocytochemistry, respectively. Furthermore, the effects of peroxisome proliferator-activated receptor-g ligands on cell proliferation and survival were investigated in OUMS-27 cells. Pioglitazone, a selective ligand for peroxisome proliferator-activated receptor-g, and 15-deoxy-D 12,14 -prostaglandin J 2 (15d-PGJ 2 ), a putative endogenous ligand for peroxisome proliferator-activated receptor-g, inhibited the proliferation of OUMS-27 cells in a dose-dependent manner. The mechanism of cytotoxic effects of 15d-PGJ 2 was via apoptosis as shown by DNA fragmentation using TUNEL stain and DNA ladder formation, and by ultrastructural analysis using transmission electron microscopy. Flow-cytometric analysis using annexin-V-fluorescein and propidium iodide detected the early change of apoptosis, as well as necrosis of OUMS-27 cells at 4 h after co-incubation with 15d-PGJ 2 . These results suggest that peroxisome proliferator-activated receptor-g may play a significant role in the pathogenesis of chondrosarcoma, and peroxisome proliferatoractivated receptor-g ligands, especially 15d-PGJ 2 , may be of therapeutic value in the treatment of human chondrosarcoma.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Inhibition of human chondrosarcoma cell growth via apoptosis by peroxisome proliferator-activated receptor-γ

et al. 2002

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“…Furthermore, TGZ and PGJ 2 affect several pathways in a PPAR␥-independent manner. TGZ up-regulates nitric oxide synthesis (19), induces the p53 pathway (20), inhibits cholesterol biosynthesis (21), and has antioxidant function (22), whereas PGJ 2 induces apoptosis (23) and affects signaling pathways that utilize ERK1/2 or NF-B (24) independent of PPAR␥. In addition, we have recently demonstrated that TGZ induces the early growth response gene EGR-1 independently of the PPAR␥ transcription factor (25).…”

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confidence: 99%

Expression of NAG-1, a Transforming Growth Factor-β Superfamily Member, by Troglitazone Requires the Early Growth Response Gene EGR-1

Baek

Kim

Nixon

et al. 2004

Journal of Biological Chemistry

129

116

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“…4 In addition, recent studies have shown that TZDs not only inhibit cell growth, but they can also induce apoptosis in VSMC. 8,9 The molecular mechanisms by which TZDs induce apoptosis in VSMC and whether they involve a PPARgdependent pathway also remain unclear.Using DNA microarray analysis, we have identified additional target genes mediating the antiproliferative and proapoptotic effects of PPARg ligands. 10,11 A biased DNA array containing 96 genes known to control the cell cycle was used to screen for nuclear targets that potentially mediate the antiproliferative activity of PPARg ligands on VSMC.…”

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confidence: 99%

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confidence: 99%

New targets for PPARγ in the vessel wall: implications for restenosis

2005

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Peroxisome proliferator-activated receptor {gamma} (PPARg), the nuclear receptor that binds the insulin-sensitizing thiazolidinediones (TZDs), is prominently upregulated in intimal vascular smooth muscle cells (VSMC) after mechanical injury to the vessel wall. Several TZD PPARg ligands have been shown to inhibit neointima formation in both normal and insulinresistant vasculature. The suppression of intimal hyperplasia by TZD PPARg ligands probably results from their activity to inhibit VSMC growth and promote apoptosis. TZDs prevent VSMC proliferation by blocking the activity of regulatory proteins, such as phosphorylation of the retinoblastoma protein (Rb). Rb functions as a G 1 gatekeeper by controlling S phase gene expression mediated by the E2F transcription factor. Consistent with their effect on Rb phosphorylation, PPARg ligands inhibit the mitogenic induction of minichromosome maintenance (MCM) proteins 6 and 7, two E2F-regulated S phase genes essential for DNA replication. PPARg ligands also induced apoptosis in VSMC, which correlated with a potent induction of GADD45, a gene implicated in controlling cell growth and survival. A constitutively active form of PPARg targeted the same cell cycle regulators as did PPARg ligands, consistent with a nuclear-receptor-dependent mechanism of action. This review will summarize mechanisms through which PPARg modulates VSMC proliferation and apoptosis suggesting that PPARg itself is a novel important regulator of cell cycle and apoptosis and may provide a new therapeutic approach to prevent restenosis. Keywords: PPARg; thiazolidinedione; vascular smooth muscle; proliferation; minichromosome maintenance protein; GADD45Peroxisome proliferator-activated receptor {gamma} (PPARg) ligands have been shown to inhibit growth of vascular and cancer cells by interfering with the expression and function of multiple cell cycle regulators. 1-6 Although many studies have focused on alterations in the regulation of cell growth as a fundamental feature during atherogenesis and neointimal hyperplasia after percutaneous coronary revascularization, it is becoming increasingly evident that perturbations in the regulation of cell death may be of equal importance. 7 In vascular smooth muscle cells (VSMC), we have previously reported that the thiazolidinedione (TZD) PPARg ligands, troglitazone (TRO) and rosiglitazone (RSG), inhibit exit from G1 into S phase of the cell cycle by attenuating retinoblastoma protein (Rb) phosphorylation. 4 As illustrated in Figure 1 decreased phosphorylation of Rb by TRO and RSG likely results from their effect to elevate levels of the cyclindependent kinase inhibitor (CDKI) p27 kip1 and reduce the activity of cyclin D-and cyclin E-dependent kinases (CDK). 4 In addition, recent studies have shown that TZDs not only inhibit cell growth, but they can also induce apoptosis in VSMC. 8,9 The molecular mechanisms by which TZDs induce apoptosis in VSMC and whether they involve a PPARgdependent pathway also remain unclear.Using DNA microarray analysis, we have identifi...

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Troglitazone induces apoptosis via the p53 and Gadd45 pathway in vascular smooth muscle cells

Cited by 104 publications

References 39 publications

Inhibition of human chondrosarcoma cell growth via apoptosis by peroxisome proliferator-activated receptor-γ

Inhibition of human chondrosarcoma cell growth via apoptosis by peroxisome proliferator-activated receptor-γ

Expression of NAG-1, a Transforming Growth Factor-β Superfamily Member, by Troglitazone Requires the Early Growth Response Gene EGR-1

New targets for PPARγ in the vessel wall: implications for restenosis

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