1. IGFBP-3 hypermethylation-derived deficiency mediates cisplatin resistance in non-small-cell lung cancer.
- Author
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Ibanez de Caceres I, Cortes-Sempere M, Moratilla C, Machado-Pinilla R, Rodriguez-Fanjul V, Manguán-García C, Cejas P, López-Ríos F, Paz-Ares L, de CastroCarpeño J, Nistal M, Belda-Iniesta C, and Perona R
- Subjects
- Antineoplastic Agents pharmacology, Azacitidine pharmacology, Base Sequence, Carcinoma, Non-Small-Cell Lung metabolism, Carcinoma, Non-Small-Cell Lung pathology, Cell Line, Tumor, Cell Survival drug effects, Gene Expression Regulation, Neoplastic drug effects, HT29 Cells, HeLa Cells, Humans, Hydroxamic Acids pharmacology, Insulin-Like Growth Factor Binding Protein 3 deficiency, Kaplan-Meier Estimate, Lung Neoplasms metabolism, Lung Neoplasms pathology, Oligonucleotide Array Sequence Analysis, Promoter Regions, Genetic genetics, RNA Interference, Reverse Transcriptase Polymerase Chain Reaction, Tumor Cells, Cultured, Carcinoma, Non-Small-Cell Lung genetics, Cisplatin pharmacology, DNA Methylation drug effects, Drug Resistance, Neoplasm genetics, Insulin-Like Growth Factor Binding Protein 3 genetics, Lung Neoplasms genetics
- Abstract
Cisplatin-based chemotherapy is the paradigm of non-small-cell lung cancer (NSCLC) treatment; however, it also induces de novo DNA-hypermethylation, a process that may be involved in the development of drug-resistant phenotypes by inactivating genes required for drug-cytotoxicity. By using an expression microarray analysis, we aimed to identify those genes reactivated in a set of two cisplatin (CDDP) resistant and sensitive NSCLC cell lines after epigenetic treatment. Gene expression, promoter methylation and CDDP-chemoresponse were further analyzed in three matched sets of sensitive/resistant cell lines, 23 human cancer cell lines and 36 NSCLC specimens. Results revealed specific silencing by promoter hypermethylation of IGFBP-3 in CDDP resistant cells, whereas IGFBP-3 siRNA interference, induced resistance to CDDP in sensitive cells (P<0.001). In addition, we found a strong correlation between methylation status and CDDP response in tumor specimens (P<0.001). Thus, stage I patients, whose tumors harbor an unmethylated promoter, had a trend towards increased disease-free survival (DFS). We report that a loss of IGFBP-3 expression, mediated by promoter-hypermethylation, results in a reduction of tumor cell sensitivity to cisplatin in NSCLC. Basal methylation status of IGFBP-3 before treatment may be a clinical biomarker and a predictor of the chemotherapy outcome, helping to identify patients who are most likely to benefit from CDDP therapy alone or in combination with epigenetic treatment.
- Published
- 2010
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