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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
PubMed

Insights

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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