Terminal differentiation of human liposarcoma cells induced by ligands for peroxisome proliferator-activated receptor γ and  the retinoid X receptor

Tontonoz, Peter; Singer, Samuel; Forman, Barry M.; Sarraf, Pasha; Fletcher, Jonathan A.; Fletcher, Christopher D.�M.; Brun, Regina P.; Mueller, Elisabetta; Altiok, Soner; Oppenheim, Heather; Evans, Ronald M.; Spiegelman, Bruce M.

doi:10.1073/pnas.94.1.237

Cited by 592 publications

(420 citation statements)

References 35 publications

(44 reference statements)

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“…In vivo study on xenograft of human tumours in immunodeficient mice followed by troglitazone treatment also provided similar results (Elstner et al, 1998;Kubota et al, 1998;Sarraf et al, 1998). Ligand-mediated PPARγ activation in those cancer cells induced cell cycle arrest (Tontonoz et al, 1997;Brockman et al, 1998;Sugimura et al, 1999;, differentiation (Tontonoz et al, 1997;Kubota et al, 1998;Mueller et al, 1998;Sarraf et al, 1998;Chang and Szabo, 2000), and apoptosis (Elstner et al, 1998;Clay et al, 1999;Keelan et al, 1999;Sato et al, 2000) or nonapoptotic cell death (Kubota et al, 1998;Butler et al, 2000). Recently, troglitazone has been used in clinical trial for the patients with advanced liposarcoma (Demetri et al, 1999) and for patients with advanced prostate cancer (Hisatake et al, 2000;Mueller et al, 2000).…”

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confidence: 74%

“…Further studies are also required to reveal whether inhibition of the p27 Kipl or p18 Ink4c increase could inhibit the growth arrest in Hep G2 as found in PK-1 cells . PPARγ ligands have been shown to drive differentiation process in various malignant cells (Tontonoz et al, 1997;Kubota et al, 1998;Sarraf et al, 1998;Chang and Szabo, 2000). When we investigated the expression of AFP and albumin in Hep G2 cells after treatment with troglitazone, we found that there was a dosedependent decrease in the AFP expression.…”

Section: Discussionmentioning

confidence: 99%

“…In vitro studies have revealed the growth inhibitory effects of PPARγ ligands on human cancer cells of different tissue origin, including liposarcoma (Tontonoz et al, 1997), adenocarcinoma of breast (Elstner et al, 1998;Mueller et al, 1998;Clay et al, 1999), colorectal adenocarcinoma and carcinoma Brockman et al, 1998;Kitamura et al, 1999), gastric adenocarcinoma (Takahashi et al, 1999;Sato et al, 2000), pancreatic carcinoma , adenocarcinoma and carcinoma of prostate (Kubota et al, 1998;Butler et al, 2000), transitional epithelial cancer of urinary bladder (Guan et al, 1999), chorio carcinoma of placenta (Keelan et al, 1999), carcinoma of lung and non-small cell lung cancer (Chang and Szabo, 2000;Tsubouchi et al, 2000) and myeloid leukaemias (Asou et al, 1999;Hirase et al, 1999;Sugimura et al, 1999). In vivo study on xenograft of human tumours in immunodeficient mice followed by troglitazone treatment also provided similar results (Elstner et al, 1998;Kubota et al, 1998;Sarraf et al, 1998).…”

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Peroxisome proliferator-activated receptor γ ligand-induced growth inhibition of human hepatocellular carcinoma

et al. 2001

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Summary Peroxisome proliferator-activated receptor γ (PPARγ) ligands have been implicated in the growth inhibition and differentiation of certain human cancers with diverse tissue origin. In this study, expression of PPARγ in human hepatocellular carcinoma (HCC) and the effect of PPARγ ligands on HCC cells were investigated in vitro using Hep G2, HuH-7, KYN-1 and KYN-2 cell lines. All cell lines were found to express functionally active PPARγ and a marked growth inhibition was induced by thiazolidinedione ligands troglitazone, and pioglitazone as well as with its natural ligand 15-deoxy-∆ 12,14 -prostaglandin J 2 . The growth inhibitory effect was associated with a dose-dependent inhibition of DNA synthesis, cell cycle progression and α fetoprotein expression.

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confidence: 74%

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confidence: 99%

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Peroxisome proliferator-activated receptor γ ligand-induced growth inhibition of human hepatocellular carcinoma

et al. 2001

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“…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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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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“…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 observed the expression of PPAR␥ and investigated the effects of TZD and their mechanism on pancreatic cancers.…”

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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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Terminal differentiation of human liposarcoma cells induced by ligands for peroxisome proliferator-activated receptor γ and the retinoid X receptor

Cited by 592 publications

References 35 publications

Peroxisome proliferator-activated receptor γ ligand-induced growth inhibition of human hepatocellular carcinoma

Peroxisome proliferator-activated receptor γ ligand-induced growth inhibition of human hepatocellular carcinoma

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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