IGFBP-3 hypermethylation-derived deficiency mediates cisplatin resistance in non-small-cell lung cancer

• Published in: Oncogene Vol. 29; no. 11; pp. 1681 - 1690
• Main Authors: IBANEZ DE CACERES, I, CORTES-SEMPERE, M, NISTAL, M, BELDA-INIESTA, C, PERONA, R, MORATILLA, C, MACHADO-PINILLA, R, RODRIGUEZ-FANJUL, V, MANGUAN-GARCIA, C, CEJAS, P, LOPEZ-RIOS, F, PAZ-ARES, L, DE CASTROCARPENO, J
• Format: Journal Article
• Language: English
• Published: Basingstoke Nature Publishing Group 18.03.2010
• Subjects: Antineoplastic Agents - pharmacology; Azacitidine - pharmacology; Base Sequence; Binding proteins; Biological and medical sciences; Cancer therapies; Carcinoma, Non-Small-Cell Lung - genetics; Carcinoma, Non-Small-Cell Lung - metabolism; Carcinoma, Non-Small-Cell Lung - pathology; Cell Line, Tumor; Cell physiology; Cell Survival - drug effects; Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes; Chemotherapy; Cisplatin; Cisplatin - pharmacology; Complications and side effects; Cytotoxicity; Deoxyribonucleic acid; DNA; DNA damage; DNA methylation; DNA Methylation - drug effects; DNA microarrays; Dosage and administration; Drug resistance; Drug Resistance, Neoplasm - genetics; Drug therapy; Epigenetics; Fundamental and applied biological sciences. Psychology; Gene expression; Gene Expression Regulation, Neoplastic - drug effects; Genetic aspects; Genetics; HeLa Cells; HT29 Cells; Humans; Hydroxamic Acids - pharmacology; Insulin-Like Growth Factor Binding Protein 3 - deficiency; Insulin-Like Growth Factor Binding Protein 3 - genetics; Insulin-like growth factor-binding protein 3; Kaplan-Meier Estimate; Lung cancer; Lung cancer, Non-small cell; Lung Neoplasms - genetics; Lung Neoplasms - metabolism; Lung Neoplasms - pathology; Medical sciences; Molecular and cellular biology; Non-small cell lung carcinoma; Oligonucleotide Array Sequence Analysis; Patients; Phenotypes; Physiological aspects; Pneumology; Promoter Regions, Genetic - genetics; Reverse Transcriptase Polymerase Chain Reaction; RNA Interference; siRNA; Small cell lung carcinoma; Tumor cell lines; Tumor Cells, Cultured; Tumors; Tumors of the respiratory system and mediastinum; Spain; Antineoplastic agent; Lung disease; NSCLC; Respiratory disease; Deficiency; hypermethylation; Malignant tumor; CDDP-resistance; non-small cell lung carcinoma; Carcinogenesis; Cisplatin; Resistance; IGFBP-3; Bronchus disease; Methylation; Cancer
• DOI: 10.1038/onc.2009.454
• ISSN: 0950-9232

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.