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

Oncogene volume 29, pages 1681–1690 (2010)Cite this article

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.

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Abbreviations

ATCC:

American Type Culture Collection

BS:

bisulfite sequencing

CDDP:

cisplatin

DFS:

disease-free survival

ECACC:

European Collection of Cell Cultures

IGFBP-3:

insulin-like growth factor binding protein-3

MSP:

methylation-specific PCR

NSCLC:

non-small-cell lung cancer

TSG:

tumor suppressor gene

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Acknowledgements

We gratefully acknowledge Javier Perez for the artwork and to J Siegfried, for the English correction of the manuscript. Ibanez de Caceres was partially supported by the Fondo de Investigacion Sanitaria (ISCIII) through the ‘Miguel Servet’ program (CP 08/000689; PI-717). Note: Supported by FIS PI06-1234, PI08-1485, PS09/00472 and Fundación Médica Mutua Madrileña.

Author information

Author notes

  1. F López-Ríos

    Present address: 7Current address: Department of Pathology, H Clara Campal, Madrid, Spain,

  2. L Paz-Ares

    Present address: 8Current address: Department of Medical Oncology, H. V. del Rocío, Sevilla, Spain,

Authors and Affiliations

  1. Oncology Research Laboratory, Research Unit, FIB-La Paz University Hospital,

    I Ibanez de Caceres

  2. Madrid, Spain

    I Ibanez de Caceres

  3. Instituto de Investigaciones Biomedicas CSIC/UAM, Translational Oncology Unit CSIC/H La Paz, Madrid, Spain

    M Cortes-Sempere, C Moratilla, R Machado-Pinilla, V Rodriguez-Fanjul, C Manguán-García & R Perona

  4. Department of Medical Oncology, La Paz University Hospital, Translational Oncology Unit CSIC/H La Paz, Madrid, Spain

    P Cejas, J de CastroCarpeño & C Belda-Iniesta

  5. Department of Pathology, 12 de Octubre Hospital, Madrid, Spain

    F López-Ríos

  6. Department of Medical Oncology, 12 de Octubre Hospital, Madrid, Spain

    L Paz-Ares

  7. Department of Pathology, La Paz University Hospital, Madrid, Spain

    M Nistal

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Correspondence to I Ibanez de Caceres.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc)

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Ibanez de Caceres, I., Cortes-Sempere, M., Moratilla, C. et al. IGFBP-3 hypermethylation-derived deficiency mediates cisplatin resistance in non-small-cell lung cancer. Oncogene 29, 1681–1690 (2010). https://doi.org/10.1038/onc.2009.454

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