Inactivation of the apoptosis effector Apaf-1 in malignant melanoma

María S. Soengas, Paola Capodieci, David Polsky, Jaume Mora, Manel Esteller, Ximena Opitz-Araya, Richard McCombie, James G. Herman, William L. Gerald, Yuri A. Lazebnik, Carlos Cordón-Cardó and Scott W. Lowe ()
Additional contact information
María S. Soengas: Cold Spring Harbor Laboratory
Paola Capodieci: Memorial Sloan Kettering Cancer Center
David Polsky: Memorial Sloan Kettering Cancer Center
Jaume Mora: Memorial Sloan Kettering Cancer Center
Manel Esteller: Johns Hopkins Oncology Center and Johns Hopkins University
Ximena Opitz-Araya: Cold Spring Harbor Laboratory
Richard McCombie: Cold Spring Harbor Laboratory
James G. Herman: Johns Hopkins Oncology Center and Johns Hopkins University
William L. Gerald: Memorial Sloan Kettering Cancer Center
Yuri A. Lazebnik: Cold Spring Harbor Laboratory
Carlos Cordón-Cardó: Memorial Sloan Kettering Cancer Center
Scott W. Lowe: Cold Spring Harbor Laboratory

Nature, 2001, vol. 409, issue 6817, 207-211

Abstract: Abstract Metastatic melanoma is a deadly cancer that fails to respond to conventional chemotherapy and is poorly understood at the molecular level1. p53 mutations often occur in aggressive and chemoresistant cancers but are rarely observed in melanoma1,2. 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 apoptosis3. 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.

Date: 2001
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DOI: 10.1038/35051606

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