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Inactivation of the apoptosis effector Apaf-1 in malignant melanoma
M S Soengas1, P Capodieci, D Polsky
1Cold Spring Harbor Laboratory, New York 11724, USA.
Nature
|February 24, 2001
Summary
Metastatic melanomas often inactivate Apaf-1, a key protein for programmed cell death. Restoring Apaf-1 levels can re-sensitize chemoresistant melanoma cells to treatment.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- Metastatic melanoma is a chemoresistant cancer with poor molecular understanding.
- p53 mutations are common in chemoresistant cancers but rare in melanoma.
- Apaf-1, a cell-death effector, mediates p53-dependent apoptosis.
Purpose of the Study:
- To investigate the role of Apaf-1 in metastatic melanoma.
- To understand the molecular mechanisms underlying chemoresistance in melanoma.
Main Methods:
- Analysis of Apaf-1 expression in metastatic melanomas.
- Investigation of Apaf-1 allelic loss and methylation.
- Treatment of melanoma cell lines with 5-aza-2'-deoxycytidine (5aza2dC).
- Gene transfer to restore Apaf-1 levels.
Main Results:
- Metastatic melanomas frequently lose Apaf-1 expression, associated with allelic loss.
- Apaf-1 loss can be reversed by methylation inhibition (5aza2dC).
- Apaf-1-negative melanomas exhibit chemoresistance and defective apoptosis.
- Restoring Apaf-1 enhances chemosensitivity and rescues apoptotic defects.
Conclusions:
- Apaf-1 inactivation is a key event in metastatic melanoma development.
- Apaf-1 loss contributes to chemoresistance and defective apoptosis in melanoma.
- Apaf-1 inactivation may explain the low frequency of p53 mutations in melanoma.
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