Activation of PPARγ inhibits cell growth and induces apoptosis in human gastric cancer cells

Takahashi, Nobuhiko; Okumura, Toshikatsu; Motomura, Wataru; Fujimoto, Yoshinori; Kawabata, Isao; Kohgo, Yutaka

doi:10.1016/s0014-5793(99)00871-6

Cited by 228 publications

(162 citation statements)

References 25 publications

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“…In vitro studies have shown that activation of the PPARg signaling pathway by ligands inhibits growth and induces differentiation and apoptosis in cultured cells of leukemia (Asou et al, 1999), bladder cancer (Guan et al, 1999), choriocarcinoma (Keelan et al, 1999), prostate cancer (Kubota et al, 1998), pancreatic carcinoma (Motomura et al, 2000), chondrosarcoma (Nishida et al, 2002), colon cancer (Sarraf et al, 1998), gastric cancer (Takahashi et al, 1999) and lung cancer (Tsubouchi et al, 2000). As the discovery of the PAX8-PPARg fusion gene in human follicular thyroid carcinoma and the demonstration of loss of PPARg transcription activity in the PAX8-PPARg fusion gene , there has been great interest in understanding the role of PPARg in the development and progression of follicular thyroid carcinoma.…”

Section: Discussionmentioning

confidence: 99%

PPARγ insufficiency promotes follicular thyroid carcinogenesis via activation of the nuclear factor-κB signaling pathway

et al. 2005

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The molecular genetic events underlying thyroid carcinogenesis are poorly understood. Mice harboring a knock-in dominantly negative mutant thyroid hormone receptor b (TRb PV/PV mouse) spontaneously develop follicular thyroid carcinoma similar to human thyroid cancer. Using this mutant mouse, we tested the hypothesis that the peroxisome proliferator-activated receptor c (PPARc) could function as a tumor suppressor in thyroid cancer in vivo. Using the offspring from the cross of TRb PV/ þ and PPARc þ /À mice, we found that thyroid carcinogenesis progressed significantly faster in TRb PV/PV mice with PPARc insufficiency from increased cell proliferation and reduced apoptosis. Reduced PPARc protein abundance led to the activation of the nuclear factor-jB signaling pathway, resulting in the activation of cyclin D1 and repression of critical genes involved in apoptosis. Treatment of TRb PV/PV mice with a PPARc agonist, rosiglitazone, delayed the progression of thyroid carcinogenesis by decreasing cell proliferation and activation of apoptosis. These results suggest that PPARc is a critical modifier in thyroid carcinogenesis and could be tested as a therapeutic target in thyroid follicular carcinoma.

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Section: Discussionmentioning

confidence: 99%

PPARγ insufficiency promotes follicular thyroid carcinogenesis via activation of the nuclear factor-κB signaling pathway

et al. 2005

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“…For reverse transcriptase-polymerase chain reaction (RT -PCR), RNA samples (5 mg) were reverse-transcribed to cDNA using reverse transcriptase (ReverTra Ace, Toyobo Co. Ltd., Osaka, Japan) and subsequently amplified by PCR using as a sense primer, 5'-TCTCTCCGTAATGGAAGACC-3' and an antisense primer, 5'-GCATTATGAGAC-ATCCCCAC-3' as previously reported (Takahashi et al, 1999). Human adult normal adipose total RNA was purchased from BioChain Institute, Inc, CA, USA (Catalogue Number 061005).…”

Section: Rna Extraction and Rt -Pcrmentioning

confidence: 99%

“…Recent studies reported that 15-deoxy-D 12,14 -prostaglandin J 2 (15d-PGJ 2 ), the most potent endogenous ligand for PPARg, and the synthetic PPARg ligand thiazolidinedione (TZD) can induce terminal differentiation and growth inhibition of human liposarcoma (Tontonoz et al, 1997), breast (Elstner et al, 1998;Yee et al, 1999), prostate (Kubota et al, 1998), colon (Sarraf et al, 1998;Kitamura et al, 1999), gastric (Takahashi et al, 1999;Sato et al, 2000), lung (Chang and Szabo, 2000;Tsubouchi et al, 2000), and pancreas (Motomura et al, 2000;Elnemr et al, 2000) cancer cells, as well as hepatoma cells (Koga et al, 2001) in vitro and in vivo. The in vivo induction of histological and biochemical differentiation of liposarcomas by clinical trial of troglitazone administration was reported by Demetri et al (1999).…”

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confidence: 99%

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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“…Several studies have shown that TZDs can lead to growth inhibition in liposarcoma, 12 breast cancer, 13,14 colon cancer, [15][16][17] prostatic cancer 18 and gastric cancer. 19 In the present study, we observed the expression of PPAR␥ and investigated the effects of TZD and their mechanism on pancreatic cancers.Pancreatic carcinoma is one of the most malignant cancers. At the time of diagnosis, over 80% of the patients have advanced regional disease or distant metastasis.…”

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confidence: 94%

Ligands for peroxisome proliferator-activated receptor ? inhibit growth of pancreatic cancers bothin vitro andin vivo

et al. 2001

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Peroxisome proliferator-activated receptor ␥ (PPAR␥) is expressed largely in adipose tissues and plays an important role in adipocyte differentiation. Several studies have recently shown that ligands of PPAR␥ could lead to growth inhibition in some malignancies. In our study, we focused on pancreatic cancers, because the prognosis of advanced pancreatic cancer has not significantly improved due to its resistance to various chemotherapeutic regimens, so that a novel strategy should be required. We show here that PPAR␥ is expressed in 5 pancreatic cancer cell lines detected in both mRNA and protein level as well as in human primary and metastatic pancreatic carcinomas examined by immunohistochemical studies. A specific ligand of PPAR␥, troglitazone, led to G1 accumulation with the increase in p27(Kip1), but not p21(Waf1/Cip1) and inhibited cellular proliferation in a pancreatic cancer cell line, Panc-1. Peroxisome proliferator-activated receptor gamma (PPAR␥) is one of the members of the nuclear hormone receptor superfamily like receptors for steroids, thyroid hormone, vitamin D and retinoic acid. 1 Like other members of this superfamily, PPAR␥ binds to DNA response element and regulates the expression of specific target genes. 2,3 15-Deoxy⌬ 12,14 prostaglandin J 2 and various polyunsaturated fatty acids have been identified as natural receptor ligands for PPAR␥ 4 -6 and the anti-diabetic thiazolidinedione (TZD) drugs as synthetic ligands. 4,7 TZDs are a new class of oral anti-diabetic agents.PPAR␥ is predominantly expressed in adipose tissue and functions as a central regulator of adipocyte differentiation. 8 The receptor is induced very early in this process and, in the presence of ligand, causes morphological changes, lipid accumulation and the activation of fat-specific genes in adipocytes. 9 PPAR␥ gene gives rise to 2 isoforms. Forced expression of PPAR␥2 activates expression of a number of typical differentiation-linked adipocyte genes, including adipocyte P2 (aP2), adipsin, lipoprotein lipase in cultured fibroblasts. 10 The common process of cell differentiation involves the slowing or complete cessation of cell growth and is referred to as terminal differentiation. On the basis of its effects on differentiation and cell-cycle regulation, induction of terminal differentiation represents an alternative convention therapy for human malignancies that may have reduced toxicity. The most successful clinical application of differentiation therapy has been the use of all-trans retinoic acid, a ligand for the retinoic acid receptor ␣ (RAR␣) in the standard treatments for acute promyelocytic leukemia. 11 Other nuclear receptors also may become the promising targets for novel therapeutic strategies in some malignancies. It has been investigated whether PPAR␥ might be a useful target for the treatment of tumors. Several studies have shown that TZDs can lead to growth inhibition in liposarcoma, 12 breast cancer, 13,14 colon cancer, [15][16][17] prostatic cancer 18 and gastric cancer. 19 In the present study, we observe...

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Activation of PPARγ inhibits cell growth and induces apoptosis in human gastric cancer cells

Cited by 228 publications

References 25 publications

PPARγ insufficiency promotes follicular thyroid carcinogenesis via activation of the nuclear factor-κB signaling pathway

PPARγ insufficiency promotes follicular thyroid carcinogenesis via activation of the nuclear factor-κB signaling pathway

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

Ligands for peroxisome proliferator-activated receptor ? inhibit growth of pancreatic cancers bothin vitro andin vivo

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