Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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Apoptosis induced by Piroxicam/Cisplatin combined treatment is triggered by p21 in mesothelioma

ABSTRACT: Here we report that piroxicam/cisplatin combined treatment exerts an apoptotic effect on mesothelioma cells. Genome-wide transcriptome analyses lead us to identify p21 as the possible apoptosis mediator acting as downstream target of the piroxicam/cisplatin treatment. To analyze the potential therapeutic effect of the piroxicam/cisplatin treatment at molecular level, and to identify gene expression pattern modifications following the combined treatment, we performed a transcriptional profiling on HGU133A arrays, using cells treated with piroxicam, cisplatin or with piroxicam and cisplatin, choosing the time exposures in which apoptosis induction was absent or evident (8 and 24 hours). Biological duplicates or triplicates were generated for each prototypic situation and data were analyzed using the oneChannelGUI Bioconductor package (Sanges et al., 2007), comparing untreated cells with cells treated in single or combined treatment. After quality controls, the complexity of the data set was reduced removing the non-significant probe sets, resulting in a total of 4,247 out of the 22,283 probe sets present in the microarray. To assess differential expression, linked to piroxicam, cisplatin- and the combined treatment we used an empirical Bayes method together with a false discovery rate (FDR) correction of the P-value. Specifically genes were selected using a corrected p-value M-bM-^IM-$0.05 and |log2(fc)| M-bM-^IM-%1. We detect a total of 536 differentially expressed genes.

ORGANISM(S): Homo sapiens

SUBMITTER: Raffaele Calogero

PROVIDER: E-GEOD-22445 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Apoptosis induced by piroxicam plus cisplatin combined treatment is triggered by p21 in mesothelioma.

Baldi Alfonso A Piccolo Maria Teresa MT Boccellino Maria Rosaria MR Donizetti Aldo A Cardillo Irene I La Porta Raffaele R Quagliuolo Lucio L Spugnini Enrico P EP Cordero Francesca F Citro Gennaro G Menegozzo Massimo M Calogero Raffaele A RA Crispi Stefania S

PloS one 20110817 8

<h4>Background</h4>Malignant mesothelioma (MM) is a rare, highly aggressive tumor, associated to asbestos exposure. To date no chemotherapy regimen for MM has proven to be definitively curative, and new therapies for MM treatment need to be developed. We have previously shown in vivo that piroxicam/cisplatin combined treatment in MM, specifically acts on cell cycle regulation triggering apoptosis, with survival increase.<h4>Methodology/principal findings</h4>We analyzed, at molecular level, the ...[more]

PMID: 21858171

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Project description:Dynamic changes in RNA and protein levels after exposure to 100µmol/L nimesulide and low-dose 0.5µmol/L cisplatin in oral cancer cells were screened to gain insights into the molecular mechanisms of cell death. After 48 hours of treatment, SCC9 and SCC25 cells were analyzed for apoptosis and necrosis by FACS, immunohistochemistry and analysis of nucleotides by HPLC. Microarray GeneChips and the iTRAQ system were used to measure changes in the whole genome and proteome. FACS and immunohistochemical analyses showed an increased number of apoptotic and necrotic SCC9 and SCC25 cells after nimesulide and cisplatin exposure. Simultaneously, ATP and the energy charge of the SCC9 cells were significantly decreased. In SCC25 cells, ATP only significantly decreased after combined nimesulide/cisplatin exposure. In the SCC9 cell line, gene and proteome analysis detected and quantified one gene, keratin 6a and 540 proteins, respectively. After combined treatment, significant upregulation of histone H2A, H2B and H4 could be found with a local discovery false rate of 0.003 and 0.0027 for histone H2A and histone H2B, respectively. Using gene and proteome mapping, we could show that combined treatment of oral cancer cells with nimesulide and low-dose cisplatin induce necrosis and early apoptosis by the intrinsic and extrinsic pathways. Our results suggest potential clinical benefits of a nimesulide/cisplatin combination rather than single cisplatin treatment for oral cancer patients. Cell culture: A squamous carcinoma cell line of the tongue, SCC9, was obtained from the American Type Culture Collection (ATCC, Rockville, Maryland, USA). The cell line was cultured in RPMI 1640 medium containing 10% fetal bovine serum and 100U/mL penicillin and 100µg/mL streptomycin (all reagents from Life Technologies Ltd, Paisley, Scotland) and incubated at 37°C in a humidified atmosphere of 5% CO2. SCC9 cells were maintained in RPMI 1640 medium and seeded at equal densities of 5x10^5 cells in 10cm tissue culture dishes. 24 hours later, cells were harvested using Trypsin/EDTA (Life Technologies Ltd, Paisley Scotland) and treated with 100µmol/L nimesulide, 0.5µmol/L cisplatin or a combination of nimesulide/cisplatin. Control dishes were treated in exactly the same way without the addition of the respective compound. The concentration of 100µmol/L for nimesulide was chosen as this concentration is in a pharmacologically relevant range for humans. cDNA microarray, hybridization and image analysis: RNA isolation and preparation of cRNA, hybridization, and scanning of the arrays were performed according to protocols of the manufacturer. Hybridization was done using three sets of human U133A GeneChips (Affymetrix, Ca, USA); only two nimesulide/cisplatin Samples are included in this submission. The arrays were scanned using the GeneArray scanner (Affymetrix). Data normalization was performed using RMA. The supplementary file 'GSE15308_sample_protocols.txt' contains detailed Sample protocols.

Dataset Information

Apoptosis induced by Piroxicam/Cisplatin combined treatment is triggered by p21 in mesothelioma

Publications

Apoptosis induced by piroxicam plus cisplatin combined treatment is triggered by p21 in mesothelioma.

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