Growth Inhibition and Differentiation of Pancreatic Cancer Cell Lines by PPARγ Ligand Troglitazone

Kawa, Shigeyuki; Nikaido, Toshio; Unno, Hiroshi; Usuda, Nobuteru; Nakayama, Kohzo; Kiyosawa, Kendo

doi:10.1097/00006676-200201000-00001

Cited by 62 publications

(43 citation statements)

References 20 publications

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“…The expression of PPAR␥ and the effect of PPAR␥ ligands on cell growth inhibition and apoptosis have been investigated in many cells including lung carcinoma (21,(23)(24)(25)(26). Although these studies showed that several PPAR␥ ligands can induce cell growth inhibition and apoptosis, little is known about the mechanism(s) mediating these effects on human lung carcinoma cells.…”

Section: Discussionmentioning

confidence: 99%

“…Although the exact mechanism of growth inhibition of carcinoma cells by PPAR␥ ligands is not known, it has been shown to be associated with alterations in the expression of the cell cyclin-dependent kinase inhibitor p21 (26,27). Consistent with this idea, we showed that PGJ2 and Cig up-regulated the expression of p21 protein and mRNA concomitant with inhibition of cyclin D1 protein and mRNA levels.…”

Section: Discussionmentioning

confidence: 99%

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Up-regulation of p21 Gene Expression by Peroxisome Proliferator-Activated Receptor γ in Human Lung Carcinoma Cells

Han

Sidell

Fisher

et al. 2004

Clinical Cancer Research

127

103

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Purpose: The peroxisome proliferator-activated receptor ␥ (PPAR␥), a ligand-dependent transcription factor belonging to the family of nuclear receptors, has been implicated in the regulation of cell growth and differentiation although the exact mechanism(s) of this activity has not been elucidated. In this study, we explored the role of PPAR␥ signaling on the control of gene expression of the cycledependent kinase inhibitor p21 in human lung carcinoma cells.Experimental Design: Using several human lung carcinoma cell lines (small and non-small carcinoma cells), we assayed for cell growth inhibition and apoptosis induction. We also assayed for p21 mRNA and protein expression by reverse transcription-PCR, real-time reverse transcription-PCR, and Western blot analysis. Nuclear protein binding activities to three response elements located in the p21 promoter [nuclear factor (NF)-B, Sp1, and NF-interleukin 6 (IL6) CAAT/enhancer binding protein (C/EBP)] were measured by gel mobility shift assays. We used transient transfection assays with p21 promoter reporter gene constructs to determine the transcriptional regulation by PPAR␥ ligands. Finally, by using p21 antisense oligonucleotides, we tested the link between PPAR␥ activation and p21 signaling in cell growth inhibition assays and by Western blot analysis.Results: We showed that the PPAR␥ ligands PGJ2 and ciglitazone inhibit the growth and induce the apoptosis of several human lung carcinoma cell lines, whereas the PPAR␣ agonist WY14643 has little effect. Treatment of lung carcinoma cells with the PPAR␥ ligands PGJ2, ciglitazone, troglizaone, and GW1929 elevated p21 mRNA and protein levels and reduced cyclin D1 mRNA levels. These results were supported by transient transfection assays, which indicated that PPAR␥ ligands increased p21 gene promoter activity in human lung carcinoma cells. In addition, p21 antisense oligonucleotides inhibited PPAR␥ ligand-induced p21 protein expression and significantly blocked lung carcinoma cell growth inhibition induced by PPAR␥ ligands. Finally, electrophoresis mobility shift experiments demonstrated that PPAR␥ ligands increased the nuclear binding activities of Sp1 and NF-IL6 (C/EBP), two transcription factors with regulatory elements in the promoter region of the p21 gene.Conclusion: PPAR␥ ligands inhibit human lung carcinoma cell growth and induce apoptosis by stimulating the cyclin-dependent kinase inhibitor p21 and by reducing cyclin D1 gene expression. The induction of p21 gene expression by PPAR␥ ligands may be mediated through increased Sp1-and NF-IL6 (C/EBP)-dependent transcriptional activation. These observations unveil a mechanism for p21 gene regulation in lung carcinoma that represents a potential target for therapy.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Up-regulation of p21 Gene Expression by Peroxisome Proliferator-Activated Receptor γ in Human Lung Carcinoma Cells

Han

Sidell

Fisher

et al. 2004

Clinical Cancer Research

127

103

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“…The PPAR␥ ligand-mediated induction of p21 WAF1/Cip1 at both the mRNA level and the protein level has previously been demonstrated in other proliferationinhibition experiments using various cell types. 12,13,32,33 It is known that functional p21 WAF1/Cip1 is localized to the nucleus. 34,35 In our previous study, the nuclear localization of p21 WAF1/Cip1 was found in the PPAR␥ ligand- treated human hepatoma cells, suggesting that the liganddependent newly synthesized p21 WAF1/Cip1 was functional.…”

Section: Discussionmentioning

confidence: 99%

Troglitazone Induces P27 Kip1 –Associated Cell–Cycle Arrest Through Down–Regulating Skp2 in Human Hepatoma Cells

et al. 2003

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Increasing evidence has confirmed that ligands for peroxisome proliferator-activated receptor ␥ (PPAR␥) exhibit antitumoral effects through inhibition of cell proliferation and induction of cell differentiation in several malignant neoplasms. Recently, we have documented the accumulation of a cyclin-dependent kinase inhibitor, p27 Kip1 , as well as an unexpected accumulation in cyclin E in G1-arrested human hepatoma cells treated with the PPAR␥ ligand troglitazone. Simultaneous accumulations in both p27 Kip1 and cyclin E are known to be characteristic phenotypes in cells derived from mice lacking Skp2, an F-box protein component of the SCF ubiquitin-ligase complex. Thus, the aim of the present study was to assess whether Skp2 might be involved in the down-regulation of p27 Kip1 in troglitazone-treated human hepatoma cells. A striking decrease in Skp2 expression and a reciprocal increase in p27 Kip1 expression were found in troglitazonetreated hepatoma cells but not in those cells treated with other PPAR␥ ligands such as pioglitazone and ciglitazone. Quantitative real-time RT-PCR analysis showed that troglitazone downregulated Skp2 at the mRNA levels. Consistently, ectopic overexpression in Skp2 brought resistance to troglitazone, resulting in a decreased population of arrested cells at the G1 phase compared with that in the mock-transfected cells. In surgically resected hepatocellular carcinoma (HCC) tissue, an increased expression in Skp2 was found in both the moderately differentiated HCCs and the poorly differentiated HCCs. In conclusion, troglitazone attenuated Skp2 expression, thereby promoting p27 Kip1 accumulation in human hepatoma cells. This therapeutic potential of the ligand may lead to new cell-cycle-based antitumor strategies for advanced HCCs.

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“…These findings are in keeping with the suggestion that PPARg acts as a tumor suppressor gene (Nakajima et al, 2001;Smith et al, 2001;Koeffler, 2003). Mechanisms of PPARg-mediated antitumor activity by Tzds demonstrated experimentally include induction of cellular differentiation (Elstner et al, 1998;Guan et al, 1999;Kitamura et al, 1999;Chang and Szabo, 2002;Kawa et al, 2002), promotion of cell cycle arrest (Brockman et al, 1998;Kitamura et al, 1999;Motomura et al, 2000;Itami et al, 2001;Koga et al, 2001;Nakashiro et al, 2001;Takashima et al, 2001;Yin et al, 2001;Kawa et al, 2002;Hong et al, 2004;Rumi et al, 2004;Chen and Harrison, 2005), antiangiogenic effects (reviewed in Alarcon de la Lastra et al, 2004) and induction of apoptosis (Elstner et al, 1998;Kubota et al, 1998;Chang and Szabo, 2000;Tsubouchi et al, 2000;Eibl et al, 2001;Takashima et al, 2001;Yang and Frucht, 2001;Lovekamp-Swan and Chaffin, 2005;Yuan et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

Novel high-affinity PPARγ agonist alone and in combination with paclitaxel inhibits human anaplastic thyroid carcinoma tumor growth via p21WAF1/CIP1

et al. 2005

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Peroxisomeproliferator-activated receptor gamma (PPARc) agonists demonstrate antitumor activity likely through transactivating genes that regulate cell proliferation, apoptosis, and differentiation. The PAX8/PPARc fusion oncogene, which is common in human follicular thyroid carcinomas appears to act via dominant negative suppression of wild-type PPARc, suggesting that it may be a tumor suppressor gene in thyroid cells. We have identified a novel high-affinity PPARc agonist (RS5444) that is dependent upon PPARc for its biological activity. This is the first report of this molecule and its antitumor activity. In vitro, the IC 50 for growth inhibition is B0.8 nM while anaplastic thyroid carcinoma (ATC) tumor growth was inhibited threeto fourfold in nude mice. siRNA against PPARc and a pharmacological antagonist demonstrated that functional PPARc was required for growth inhibitory activity of RS5444. RS5444 upregulated the cell cycle kinase inhibitor, p21 WAF1/CIP1 . Silencing p21 WAF1/CIP1 rendered cells insensitive to RS5444. RS5444 plus paclitaxel demonstrated additive antiproliferative activity in cell culture and minimal ATC tumor growth in vivo. RS5444 did not induce apoptosis but combined with paclitaxel, doubled the apoptotic index compared to that of paclitaxel. Our data indicate that functional PPARc is a molecular target for therapy in ATC. We demonstrated that RS5444, a thiazolidinedione (Tzd) derivative, alone or in combination with paclitaxel, may provide therapeutic benefit to patients diagnosed with ATC.

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Growth Inhibition and Differentiation of Pancreatic Cancer Cell Lines by PPARγ Ligand Troglitazone

Abstract: Troglitazone had growth inhibitory and differentiation induction effects on the pancreatic cancer cell lines through the upregulation of p21 expression, suggesting that ligand activation of PPAR gamma is a new molecular target for effective therapy against pancreatic cancer.

Cited by 62 publications

References 20 publications

Up-regulation of p21 Gene Expression by Peroxisome Proliferator-Activated Receptor γ in Human Lung Carcinoma Cells

Up-regulation of p21 Gene Expression by Peroxisome Proliferator-Activated Receptor γ in Human Lung Carcinoma Cells

Troglitazone Induces P27 Kip1 –Associated Cell–Cycle Arrest Through Down–Regulating Skp2 in Human Hepatoma Cells

Novel high-affinity PPARγ agonist alone and in combination with paclitaxel inhibits human anaplastic thyroid carcinoma tumor growth via p21WAF1/CIP1

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