Inactivation of the apoptosis effector Apaf-1 in malignant melanoma

Soengas, M. S., Capodieci, P., Polsky, D., Mora, J., Esteller, M., Opitz-Araya, X., McCombie, R., Herman, J. G., Gerald, W. L., Lazebnik, Y. A., Cordon-Cardo, C., Lowe, S. W. (2001) Inactivation of the apoptosis effector Apaf-1 in malignant melanoma. Nature, 409 (6817). pp. 207-211. ISSN 0028-0836

URL: http://www.ncbi.nlm.nih.gov/pubmed/11196646
DOI: 10.1038/35051606

Abstract

Metastatic melanoma is a deadly cancer that fails to respond to conventional chemotherapy and is poorly understood at the molecular level. p53 mutations often occur in aggressive and chemoresistant cancers but are rarely observed in melanoma. Here we show that metastatic melanomas often lose Apaf-1, a cell-death effector that acts with cytochrome c and caspase-9 to mediate p53-dependent apoptosis. Loss of Apaf-1 expression is accompanied by allelic loss in metastatic melanomas, but can be recovered in melanoma cell lines by treatment with the methylation inhibitor 5-aza-2'-deoxycytidine (5aza2dC). Apaf-1-negative melanomas are invariably chemoresistant and are unable to execute a typical apoptotic programme in response to p53 activation. Restoring physiological levels of Apaf-1 through gene transfer or 5aza2dC treatment markedly enhances chemosensitivity and rescues the apoptotic defects associated with Apaf-1 loss. We conclude that Apaf-1 is inactivated in metastatic melanomas, which leads to defects in the execution of apoptotic cell death. Apaf-1 loss may contribute to the low frequency of p53 mutations observed in this highly chemoresistant tumour type.

Item Type: Paper
Uncontrolled Keywords: Antineoplastic Agents Apoptosis Apoptotic Protease-Activating Factor 1 Caspase 9 Caspases Chromosomes, Human, Pair 12 Cloning, Molecular DNA Methylation DNA, Neoplasm Doxorubicin Gene Expression Regulation, Neoplastic Genes, Tumor Suppressor Genes, p53 Humans Loss of Heterozygosity Melanoma Mutation Proteins Tumor Cells, Cultured
Subjects: diseases & disorders > cancer
organs, tissues, organelles, cell types and functions > cell types and functions > cell functions > apoptosis
organs, tissues, organelles, cell types and functions > cell types and functions > cell functions
organs, tissues, organelles, cell types and functions > cell types and functions
diseases & disorders > cancer > cancer types > melanomas
diseases & disorders > cancer > cancer types
CSHL Authors:
Communities: CSHL labs > Labeznik lab
CSHL labs > Lowe lab
CSHL labs > McCombie lab
Depositing User: Matt Covey
Date Deposited: 12 Dec 2012 17:29
Last Modified: 12 Dec 2012 17:29
Related URLs:
URI: http://repository.cshl.edu/id/eprint/26385

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