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Apoptosis in Human Oral Squamous Cell Carcinomas is Induced by 15-Deoxy-^12,14-Prostaglandin J₂ but not by Troglitazone

¹ First Department of Oral and Maxillofacial Surgery, Osaka Dental University, Hirakata, Japan;
² Department of Pharmacology, Osaka Dental University, 8-1, Kuzuhahanazono-cho, Hirakata, Osaka 573-1121, Japan; and
³ Institute of Clinical Medicine and Research, Jikei University School of Medicine, Kashiwa, Japan;

*corresponding author, date{at}cc.osaka-dent.ac.jp

	ABSTRACT

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15-deoxy-^12,14-prostaglandin J₂ (15-d-PGJ₂) and troglitazone have been shown to induce apoptosis in several carcinoma cell lines. However, apoptotic signaling pathways of these agents are poorly understood. We tested the hypothesis that peroxisome proliferator-activated receptor- ligands such as these two agents will induce caspase-mediated apoptosis in human oral squamous cell carcinomas (SCC). Treatment of these cell lines with 15-d-PGJ₂ or troglitazone decreased cell viability in a time- and dose-dependent manner. 15-d-PGJ₂, but not troglitazone, induced apoptosis, and this effect was time-dependent. Exposure of cells to 20 µM of 15-d-PGJ₂ initiated early cytochrome c release, followed by late caspase activation. Furthermore, co-treatment with caspase inhibitors such as Z-VAD-FMK or Z-DEVD-FMK of oral SCC cells that had been treated with 20 µM of 15-d-PGJ₂ blocked apoptosis. Our study demonstrates that treatment with 15-d-PGJ₂, but not troglitazone, induces apoptosis in human SCC cell lines, and 15-d-PGJ₂ appears to work through cytochrome c release and caspase activation.

KEY WORDS: 15-deoxy-^12,14-prostaglandin J₂ • troglitazone • apoptosis • oral squamous cell carcinoma • peroxisome proliferator-activated receptor-

	INTRODUCTION

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Several investigators have shown that a novel biologically active prostaglandin of the J₂ series, 15-deoxy-^12,14-prostaglandin J₂ (15-d-PGJ₂) (Keelan et al., 1999; Clay et al., 2000; Eibl et al., 2001), and a synthetic drug, troglitazone (Elstner et al., 1998; Takahashi et al., 1999; Tsubouchi et al., 2000), induce apoptosis in several carcinoma cell lines, and that they are potent activators of peroxisome proliferator-activated receptor- (PPAR-) (Forman et al., 1995; Kliewer et al., 1995). 15-d-PGJ₂ is a downstream metabolite of prostaglandin D₂ and is produced by dehydration of prostaglandin D₂. Troglitazone has been used in drug trials in patients with insulin-resistant diabetes mellitus. Recent studies revealed that 15-d-PGJ₂ and troglitazone lead to inhibition of phorbol ester-induced increases in nitric oxide and in macrophage-derived cytokines such as TNF-, IL-1, and IL-6. These agents also inhibit gene expression in part by antagonizing the activities of transcription factors such as AP-1 and NF-B (Jiang et al., 1998; Ricote et al., 1998).

Cancer of the oral cavity is a very common disease throughout the world, and squamous cell carcinoma (SCC) is clinically the most significant malignant neoplasm (Parkin et al., 1993). At late stages of malignancy, oral SCC is very resistant to cancer-therapy-mediated apoptosis (Wong et al., 1996; Dong et al., 2001). To our knowledge, the effects of 15-d-PGJ₂ and troglitazone in human SCC cells have not been reported previously. The hypothesis of the present work is that PPAR- ligands such as 15-d-PGJ₂ and troglitazone induce caspase-mediated apoptosis in human oral SCC. Analysis of our data demonstrates that 15-d-PGJ₂ and troglitazone lead to inhibition of the growth of human oral SCC cells, and that the growth inhibition by 15-d-PGJ₂ but not by troglitazone is mediated by apoptosis involving cytochrome c release from mitochondria and caspase activation.

	MATERIALS & METHODS

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Cells and Culture
SAS and HSC-4 cell lines, which were obtained from Health Science Research Resources Bank (Osaka, Japan), were established from spontaneously arising human oral SCC (Momose et al., 1989; Takahashi et al., 1989). Cells were kept in culture at 37°C in a 5% CO₂ atmosphere and 100% humidity. SAS cells were cultured in 50% Dulbecco’s modified Eagle’s medium with 50% Ham’s F12 medium, 10% fetal calf serum, 100 units/mL of penicillin G, and 0.1 mg/mL of streptomycin. HSC-4 cells were cultured in Eagle’s minimal essential medium with 10% fetal calf serum, 100 units/mL of penicillin G, and 0.1 mg/mL of streptomycin.

Western Blot Analysis
Cells grown in a 35-mm dish underwent lysis with sample buffer (20% glycerol, 10% 2-mercaptoethanol, 4% SDS, 125 mM Tris-HCl, pH 6.8, 0.04% bromphenol blue) and were boiled for 5 min. Samples were fractionated on 7.5% SDS-PAGE and transferred to nitrocellulose membranes. Membranes were probed with monoclonal antibodies against human PPAR- (sc-7273; Santa Cruz Biotechnology, Santa Cruz, CA, USA) at a dilution of 1:200 for 1 hr. Membranes were incubated with a horseradish-peroxidase-conjugated anti-mouse immunoglobulin as a secondary antibody (ZYMED, San Francisco, CA, USA) at a dilution of 1:2000 for 1 hr. After additional washes, membranes were treated with an enhanced chemiluminescence system (Amersham Pharmacia Biotech, Piscataway, NJ, USA).

Immunocytochemistry
Cells were plated in LabTech chamber slides (Nunc, Roskilde, Denmark) at a density of 5 x 10⁴ cells/slide and were allowed to grow for 24 hrs. Then the cells were fixed with cold methanol/acetone (1:1, v/v) for 5 min, and immunocytochemical staining was performed with an LSAB kit (DAKO, Kyoto, Japan). The primary antibody against human PPAR- (1 µg/mL) (sc-7273; Santa Cruz Biotechnology, Santa Cruz, CA, USA) or normal mouse serum (1 µg/mL) was used. Immunoreactivity was visualized by immersion in 0.05 M Tris-HCl buffer containing 3.3'-diaminobenzidine tetrahydrochloride and hydrogen peroxide.

Evaluation of the in vitro Effects of 15-d-PGJ₂ and Troglitazone
In a 96-well microplate, 1 x 10⁴ cells/well were incubated with 1-40 µM of 15-d-PGJ₂ (Alexis Biochemicals, San Diego, CA, USA) or troglitazone (gift of Sankyo Pharmaceuticals, Tokyo, Japan) for the indicated periods of time. Cell viability was determined by a modified MTT assay (WST-8 assay: Dojindo, Kumamoto, Japan) (Tominaga et al., 1999), and data are presented as a percentage of viability values seen under control culture conditions. For the WST-8 assay, a 10-µL quantity of WST-8 dye solution was added directly to 100 µL of culture medium per well, and the absorbance at 450 nm was measured on the microplate reader.

Detection of Apoptosis
The TUNEL assay was performed with the use of an Apoptosis Detection Kit (Wako, Osaka, Japan) in accordance with the manufacturer’s instructions. For the assessment of cytosolic histone-bound DNA fragments, an ELISA kit (Cell Death Detection ELISA^PLUS, Roche Diagnostics GmbH, Mannheim, Germany) was used. Briefly, 1 x 10⁴ cells/well were incubated in a 96-well microplate for the indicated periods of time in the presence of 20 µM 15-d-PGJ₂ with or without Z-VAD-FMK or Z-DEVD-FMK. Cells underwent lysis, and the lysate was added to streptavidin-coated 96-well plates, to which was added a mixture of biotinylated anti-histone and peroxidase-coupled anti-DNA antibodies. After the plates were incubated for 2 hrs and washed, the amount of cytoplasmic nucleosome was quantified by determination of the peroxidase staining retained in the immunocomplex, which was determined spectrophotometrically with 2,2' -azino-di[3-ethylbenzothiazoline-sulfonate] as the substrate at an absorbance of 405 nm.

Measurement of Caspase Protease Activity
To measure the enzymatic activity of caspase proteases, we used caspase fluorometric assay kits (R&D systems, Minneapolis, MN, USA). Briefly, cells treated with 20 µM 15-d-PGJ₂ underwent lysis in lysis buffer on ice for 10 min. The activities of caspase-3, -8, or -9-like proteases were measured by proteolytic cleavage of substrates, including DEVD-AMC (caspase-3 substrate), IETD-AFC (caspase-8 substrate), or LEHD-AFC (caspase-9 substrate), respectively. These fluorogenic substrates were solubilized in an assay buffer. After incubation at 37°C for 60 min in the dark, fluorescence from the lysates was measured with a fluorometer at dual wavelengths (400-nm excitation and 508-nm emission).

Determination of Cytochrome c Release from Mitochondria
Five x 10⁵ cells/35-mm dish were incubated with 20 µM 15-d-PGJ₂ for the indicated periods of time. Cells were harvested, and cell pellets were re-suspended in 400 µL ice-cold buffer containing 20 mM HEPES, pH 7.5, 10 mM KCl, 1.5 mM MgCl₂, 1 mM EDTA, 1 mM DTT, and 1 mM PMSF. Cells were homogenized with the use of a glass dounce homogenizer and a B pestle. Lysate was centrifuged at 10,000 x g for 10 min, and the resultant supernatant was further centrifuged at 100,000 x g for 1 hr. The supernatant from the final centrifugation was used as the cytosolic extract.

For cytosolic cytochrome c assessment, an ELISA kit (Quantikine, R&D Systems Inc., Minneapolis, MN, USA) was used in accordance with the manufacturer’s instructions. After color development had stopped, the absorbance at 450 nm was measured on the microplate reader.

Statistical Analysis
Data are expressed as mean ± SD for triplicate determinations. Statistical significance was determined by one-way ANOVA, followed by the multiple-range test for comparison of means. P values less than 0.05 were considered significant.

	RESULTS

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Expression of PPAR- Protein in Human Oral SCC Cell Lines
To determine if SAS and HSC-4 cells express PPAR- protein, we performed Western blotting and immunocytochemistry. By Western blotting, PPAR- ( 58 kDa) was detected in SAS and HSC-4 cells (Fig. 1A). By immunocytochemical staining, the protein was uniformly localized to nuclei in all cells in SAS and HSC-4 cell cultures (Fig. 1B). Staining was significantly abolished in the presence of a blocking peptide (data not shown).

View larger version (73K): [in this window] [in a new window]   Figure 1. PPAR- protein expression in SAS and HSC-4 cells. (A) Western blot analysis. (B) Immunocytochemistry. Results shown are from one representative experiment from a total of 3 performed. Scale bar = 10 µm.

View larger version (29K): [in this window] [in a new window]   Figure 2. Effects of 15-d-PGJ2 and troglitazone on cell viability. Cells were incubated with various concentrations of 15-d-PGJ2 and trogiltazone for 36 hrs (A) and with 20 µM 15-d-PGJ2 and troglitazone for the indicated periods of time (B). Cell viability was determined by a modified MTT assay and expressed as a percentage of viability under control culture conditions. Data are expressed as mean ± SD (n = 3). *p < 0.05, **p < 0.01.

View larger version (51K): [in this window] [in a new window]   Figure 3. Detection of apoptosis in human oral SCC cell lines. (A) TUNEL staining in human oral SCC cell lines. A TUNEL assay was performed 24 hrs after 20 µM of 15-d-PGJ2 or troglitazone treatment. The results shown are from a representative experiment from a total of 3 that were performed. Scale bar = 10 µm. (B) Effect of 15-d-PGJ2 or troglitazone on intracellular nucleosome enrichment. The nucleosome concentration after 20 µM of 15-d-PGJ2 or troglitazone treatment was examined with a cell-death detection kit for the indicated periods of time. Control cells were assigned a value of 1, and other values were expressed relative to these and were plotted against the time after treatment. Data are expressed as mean ± SD (n = 3). *p < 0.05, **p < 0.01.

Involvement of Caspases in 15-d-PGJ₂-induced Apoptosis
To elucidate further the mechanisms involved in the observed apoptosis, we measured intracellular caspase-3, -8, and -9 activities at various time points (Fig. 4). Caspase-3 activation in SAS and HSC-4 cells increased as early as 3 hrs after treatment. In SAS cells, it reached maximal levels by 12 hrs, which was 11-fold greater than that of control, and decreased thereafter. In HSC-4 cells, it was highest at 24 hrs, which was an increase to eight-fold greater than normal. Caspase-9 activation in SAS and HSC-4 cells was increased to 2.4- and 2.6-fold, respectively, of unstimulated levels. In contrast, caspase-8 activation in SAS and HSC-4 cells after treatment did not differ significantly.

View larger version (23K): [in this window] [in a new window]   Figure 4. Effects on apoptotic signaling pathways by 15-d-PGJ2. Control cells were assigned a value of 1, and other values were expressed relative to these and were plotted against the time after 15-d-PGJ2 treatment. Data are expressed as mean ± SD (n = 3). *p < 0.05, **p < 0.01. (A) Caspase activation induced by 15-d-PGJ2. Cells were incubated with 20 µM 15-d-PGJ2 and troglitazone for the indicated periods of time. (B) Effects of caspase inhibitors on 15-d-PGJ2-induced apoptosis. Cells were treated with 20 µM 15-d-PGJ2 in the presence or absence of Z-VAD-FMK (2.5-20 µM), or Z-DEVD-FMK (2.5-20 µM) for 24 hrs. Then cells were processed for detection of fragmented mono- and oligonucleosomes by ELISA. (C) Cytochrome c release from mitochondria. Cells were incubated with 20 µM 15-d-PGJ2 for the indicated periods of time.

Cytochrome c Release from Mitochondria
Cytochrome c release from mitochondria and subsequent activation of caspases are closely associated with induction and execution of the apoptotic process. To determine whether activation of caspases occurs prior to or after cytochrome c release, we analyzed cytochrome c in the cytosolic fraction using a human cytochrome c immunoassay (Fig. 6). In SAS and HSC-4 cells, cytochrome c release from mitochondria was time-dependent and maximal at 6 hrs after 15-d-PGJ₂ treatment, indicating that cytochrome c release is an early event in 15-d-PGJ₂-induced apoptosis.

	DISCUSSION

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Our results show that PPAR- protein was expressed in two different human oral SCC cell lines. Both 15-d-PGJ₂ and troglitazone decreased cell viability in these cell lines. Interestingly, cells treated with low concentrations of 15-d-PGJ₂ showed a slightly increased cell viability, whereas high concentrations of this compound produced the opposite effect, a marked decline in cell viability. A similar observation has been described elsewhere (Clay et al., 2000).

To determine the underlying mechanisms of the growth-inhibitory effect of 15-d-PGJ₂ and troglitazone, we investigated whether 15-d-PGJ₂ and troglitazone act by inducing apoptosis of human oral SCC cells. Apoptosis was observed in SAS and HSC-4 cells that were treated with 15-d-PGJ₂. In contrast, treatment of human oral SCC cells with troglitazone did not induce apoptosis. Furthermore, 15-d-PGJ₂ but not troglitazone affected the number of floating cells and did so dose-dependently. These results suggest that the mechanism for the growth inhibition of human oral SCC cells is different for 15-d-PGJ₂ and troglitazone. Other investigators have also suggested that cell growth inhibition by 15-d-PGJ₂ is mediated by both PPAR--dependent and PPAR--independent mechanisms, such as inhibitory effects on transcription factors such as AP-1 and NF-B, and that new gene synthesis is required for 15-d-PGJ₂-induced apoptosis (Jiang et al., 1998; Ricote et al., 1998; Clay et al., 2001; Li et al., 2001). Whether apoptosis induced by 15-d-PGJ₂ is mediated by PPAR--dependent or PPAR--independent pathways remains to be determined.

The activation and action of caspases are believed to be pivotal in the mechanism of apoptosis. Several lines of evidence suggest that the increase in apoptosis by treatment of cells with 15-d-PGJ₂ is dependent on caspase-3 (Chattopadhyay et al., 2000; Clay et al., 2001). In other cell lines, 15-d-PGJ₂ has been shown to induce apoptosis by a caspase-3-independent mechanism (Keelan et al., 1999; Eibl et al., 2001), suggesting that the apoptosis process varies among different cell lines. Thus, we investigated the involvement of the caspase pathway in 15-d-PGJ₂-induced apoptosis in human oral SCC cells. Caspase-3 activation in human oral SCC cells increased after 15-d-PGJ₂ treatment. This finding was confirmed by experiments utilizing the caspase inhibitor Z-DEVD-FMK, which blocked 15-d-PGJ₂-mediated apoptosis.

Interestingly, 15-d-PGJ₂ considerably increased the release of cytochrome c from mitochondria at an early stage of apoptosis in SAS and HSC-4 cells. Results from our study demonstrated that treatment of human oral SCC cells with 15-d-PGJ₂ initiates early cytochrome c release, followed by late caspase activation.

In conclusion, we have presented the first report of apoptosis induced by 15-d-PGJ₂ in human oral SCC cell lines; troglitazone-mediated cell death in these cell lines does not occur by apoptosis. From our studies, the mechanism of 15-d-PGJ₂-induced apoptosis appears to involve release of cytochrome c into the cytoplasm and caspase activation, although further studies are required for a more complete characterization of the processes involved. The study of the growth-inhibitory effects of these agents will contribute to increased understanding of the critical signaling pathways in oral SCC carcinogenesis.

Received February 17, 2003; Last revision June 19, 2003; Accepted July 6, 2003

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