PPAR-γ ligands inhibit growth of human esophageal adenocarcinoma cells through induction of apoptosis, cell cycle arrest and reduction of ornithine decarboxylase activity

Takashima, Takashi; Fujiwara, Yasuhiro; Higuchi, Kazuhide; Yano, Yoshihisa; Hasuma, Tadayoshi; Otani, Shuzo

doi:10.3892/ijo.19.3.465

Cited by 58 publications

(60 citation statements)

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“…Numerous studies have demonstrated that troglitazone (TRO), a synthetic PPARg ligand, causes growth inhibition, induces differentiation, and triggers apoptosis of various human malignant cells (Asou et al, 1999;Clay et al, 1999;Demetri et al, 1999;Sugimura et al, 1999;Hisatake et al, 2000;Rumi et al, 2001;Takashima et al, 2001;Begum et al, 2002;Yoshizawa et al, 2002). TRO inhibits proliferation of MCF-7 breast cancer cells by inducing cell cycle arrest and causing apoptosis (Yin et al, 2001).…”

Section: Introductionmentioning

confidence: 99%

Signaling pathways involved in induction of GADD45 gene expression and apoptosis by troglitazone in human MCF-7 breast carcinoma cells

et al. 2004

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We previously reported that the PPARc agonist troglitazone (TRO) inhibits proliferation and induces apoptosis in human MCF-7 breast carcinoma cells. To understand the mechanisms of antiproliferative and pro-apoptotic effects of TRO, we screened a limited DNA array containing 23 genes involved in regulating either the cell cycle and/or apoptosis. Four of the 23 genes screened exhibited regulation by TRO, with growth arrest and DNA damage-inducible gene 45 (GADD45) being the most strongly upregulated. TRO induced GADD45 mRNA expression in a time-and dose-dependent manner. Depletion of GADD45 by siRNA abrogated TROinduced apoptosis in MCF-7 cells demonstrating the physiological relevance of GADD45 upregulation. Signaling pathways mediating TRO-induced GADD45 were also investigated. Several mitogen-activated protein kinase (MAPK) pathways were involved in the induction of GADD45 by TRO. Inhibition of the c-jun N-terminal kinase MAPK pathway by SP600125 partially abolished TRO-induced GADD45 mRNA, and protein expression and apoptosis. In contrast, inhibition of the p38 MAPK pathway by SB203580, or through overexpression of a dominant-negative mutant of p38 MAPK, augmented GADD45 mRNA induction and GADD45 promoter activation as well as cell apoptosis by TRO. Blockade of the extracellular signal-regulated kinase MAPK pathway by PD98059 also enhanced TRO's effects on GADD45 and apoptosis. Two other PPARc agonists pioglitazone and rosiglitazone did not induce GADD45 expression. Our finding of GADD45 induction by TRO may provide a new insight concerning the mechanisms for TRO's antiproliferative and pro-apoptotic effects in breast cancer cells.

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Section: Introductionmentioning

confidence: 99%

Signaling pathways involved in induction of GADD45 gene expression and apoptosis by troglitazone in human MCF-7 breast carcinoma cells

et al. 2004

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“…For example, troglitazone, a peroxisome proliferator-activated receptor gamma (PPAR-gamma) ligand, has been found to reduce ODC activity in human esophageal adenocarcinoma cells. 162 In vitro treatment of a human esophageal adenocarcinoma cell line with troglitazone significantly inhibited cell growth and induced apoptosis, events which would limit the growth of neoplastic cells in vivo. 162 Moreover, the in vitro effect of troglitazone was specific for esophageal adenocarcinoma cells as there was no effect of troglitazone on cell growth, apoptosis, or ODC activity in an esophageal squamous cell carcinoma cell line.…”

Section: Inhibition Of Ornithine Decarboxylasementioning

confidence: 99%

“…162 In vitro treatment of a human esophageal adenocarcinoma cell line with troglitazone significantly inhibited cell growth and induced apoptosis, events which would limit the growth of neoplastic cells in vivo. 162 Moreover, the in vitro effect of troglitazone was specific for esophageal adenocarcinoma cells as there was no effect of troglitazone on cell growth, apoptosis, or ODC activity in an esophageal squamous cell carcinoma cell line. 162 Taken together, these data suggest that ODC inhibition may be a promising chemopreventive strategy in patients with Barrett esophagus, but well designed, controlled clinical trials are needed before any of the available ODC inhibitors can be recommended for clinical use.…”

Section: Inhibition Of Ornithine Decarboxylasementioning

confidence: 99%

Concepts in the Prevention of Adenocarcinoma of the Distal Esophagus and Proximal Stomach

Souza

Spechler

2005

CA: A Cancer Journal for Clinicians

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For decades, the incidence rates for squamous cell carcinoma of the esophagus and adenocarcinoma of the distal stomach have been declining while the rates for adenocarcinomas of the esophagus and gastric cardia have increased profoundly. Recent studies have shown that the gastroesophageal junction (GEJ) is regularly exposed to concentrated gastric acid and to a variety of nitrosating species, noxious agents that may contribute to carcinogenesis in this region. For adenocarcinomas that straddle the GEJ, it can be difficult to determine whether the tumor originated in the esophagus or in the gastric cardia. This classification problem hampers studies on the epidemiology and pathogenesis of GEJ tumors. Current concepts in the prevention of cancers of the distal esophagus and proximal stomach have emerged from advances in our understanding of the specific molecular events that occur during the evolution of these tumors. This report reviews those events and focuses on current concepts in the prevention of adenocarcinomas at the GEJ. The similarities and differences in risk factors, molecular pathogenesis, and in preventive strategies for adenocarcinomas of the esophagus and gastric cardia are highlighted. (CA Cancer J Clin 2005;55:334-351.)

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“…Thereafter, culture medium was added and cells were centrifuged at 500 g for 10 min, followed by two additional washing steps in PBS. The cell pellets were then resuspended in 1 ml of homogenization buffer consisting of potassium phosphate buffer (0.1 M, pH 7.4), 13 Complete TM protease inhibitor cocktail, and sucrose (0.25 M). The samples were then sonicated for 3 3 20 s at 100 W with a ultrasonic cell disruptor (Microson TM ; SPI Supplies, West Chester, PA) and subjected to differential centrifugation at 1,000 g for 10 min, 10,000 g for 15 min, and 100,000 g for 1.5 h at 48C.…”

Section: Preparation Of Cellular Fractionsmentioning

confidence: 99%

“…In a variety of malignancies including CRC, 15d-PGJ 2 displays growth-inhibitory and proapoptotic actions (13,14). 15d-PGJ 2 is a CyPG of the J 2 series derived from PGD 2 .…”

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confidence: 99%

15-deoxy-Δ12,14-prostaglandin J2 inhibits the expression of microsomal prostaglandin E synthase type 2 in colon cancer cells

Schröder

Yudina

Sabirsh

et al. 2006

Journal of Lipid Research

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Prostaglandin (PG) E 2 (PGE 2 ) plays a predominant role in promoting colorectal carcinogenesis. The biosynthesis of PGE 2 is accomplished by conversion of the cyclooxygenase (COX) product PGH 2 by several terminal prostaglandin E synthases (PGES). Among the known PGES isoforms, microsomal PGES type 1 (mPGES-1) and type 2 (mPGES-2) were found to be overexpressed in colorectal cancer (CRC); however, the role and regulation of these enzymes in this malignancy are not yet fully understood. Here, we report that the cyclopentenone prostaglandins (CyPGs) 15-deoxy-D 12,14 -PGJ 2 and PGA 2 downregulate mPGES-2 expression in the colorectal carcinoma cell lines Caco-2 and HCT 116 without affecting the expression of any other PGES or COX. Inhibition of mPGES-2 was subsequently followed by decreased microsomal PGES activity. These effects were mediated via modulation of the cellular thiol-disulfide redox status but did not involve activation of the peroxisome proliferator-activated receptor g or PGD 2 receptors. CyPGs had antiproliferative properties in vitro; however, this biological activity could not be directly attributed to decreased PGES activity because it could not be reversed by adding PGE 2 . Our data suggest that there is a feedback mechanism between PGE 2 and CyPGs that implicates mPGES-2 as a new potential target for pharmacological intervention in CRC.-Schröder,

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PPAR-γ ligands inhibit growth of human esophageal adenocarcinoma cells through induction of apoptosis, cell cycle arrest and reduction of ornithine decarboxylase activity

Cited by 58 publications

References 0 publications

Signaling pathways involved in induction of GADD45 gene expression and apoptosis by troglitazone in human MCF-7 breast carcinoma cells

Signaling pathways involved in induction of GADD45 gene expression and apoptosis by troglitazone in human MCF-7 breast carcinoma cells

Concepts in the Prevention of Adenocarcinoma of the Distal Esophagus and Proximal Stomach

15-deoxy-Δ12,14-prostaglandin J2 inhibits the expression of microsomal prostaglandin E synthase type 2 in colon cancer cells

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