Key role of mitochondria in cerulenin-mediated apoptosis

Cell Death Differ. 2002 Sep;9(9):1017-25. doi: 10.1038/sj.cdd.4401055.

Abstract

Cerulenin, a fungal metabolite, is known to be a specific inhibitor of fatty acid synthase. Here we report that cerulenin is an effective inducer of apoptosis in different wild-type p53 and mutant p53 tumor cell lines, whereas normal human keratinocytes and fibroblasts are resistant to the apoptotic effect. To get more insight into the mechanisms of how cerulenin induces apoptosis we investigated several signal transduction molecules, including p53, p73, p21/WAF1, Bax, cytochrome c, and caspases 3 and 9. Our data strongly indicate that mitochondria play a key role in the cerulenin-mediated pathway. Bax overexpression correlated with the extent of apoptosis and appears to be regulated in a p53-independent manner. The significance of the mitochondrial pathway for the cerulenin-mediated apoptosis was confirmed by the rapid mitochondrial release of cytochrome c both in wild-type p53 and mutant cell lines. Interestingly, the rapid release of cytochrome c was not accompanied by a breakdown of the mitochondrial potential. Instead, the complete disruption of the mitochondrial function coincided with the appearance of a p18 kDa cleavage product of Bax.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis / drug effects
  • Apoptosis / physiology*
  • Caspase 3
  • Caspase 9
  • Caspases / drug effects
  • Caspases / metabolism
  • Cerulenin / pharmacology*
  • Cyclin-Dependent Kinase Inhibitor p21
  • Cyclins / drug effects
  • Cyclins / metabolism
  • Cytochrome c Group / drug effects
  • Cytochrome c Group / metabolism
  • Cytotoxins / pharmacology*
  • DNA-Binding Proteins / drug effects
  • DNA-Binding Proteins / metabolism
  • Eukaryotic Cells / drug effects
  • Eukaryotic Cells / metabolism*
  • Fatty Acid Synthases / antagonists & inhibitors
  • Fatty Acid Synthases / genetics
  • Fatty Acid Synthases / metabolism
  • Gene Expression Regulation, Enzymologic / drug effects
  • Gene Expression Regulation, Enzymologic / genetics
  • Genes, Tumor Suppressor
  • Humans
  • Membrane Potentials / drug effects
  • Membrane Potentials / physiology
  • Mitochondria / drug effects
  • Mitochondria / metabolism*
  • Mutation / drug effects
  • Mutation / genetics
  • Neoplasms / drug therapy
  • Neoplasms / metabolism*
  • Nuclear Proteins / drug effects
  • Nuclear Proteins / metabolism
  • Proto-Oncogene Proteins / drug effects
  • Proto-Oncogene Proteins / metabolism
  • Proto-Oncogene Proteins c-bcl-2*
  • Signal Transduction / drug effects
  • Signal Transduction / physiology
  • Tumor Cells, Cultured / drug effects
  • Tumor Cells, Cultured / metabolism*
  • Tumor Protein p73
  • Tumor Suppressor Protein p53 / deficiency
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Proteins
  • bcl-2-Associated X Protein

Substances

  • BAX protein, human
  • CDKN1A protein, human
  • Cyclin-Dependent Kinase Inhibitor p21
  • Cyclins
  • Cytochrome c Group
  • Cytotoxins
  • DNA-Binding Proteins
  • Nuclear Proteins
  • Proto-Oncogene Proteins
  • Proto-Oncogene Proteins c-bcl-2
  • Tumor Protein p73
  • Tumor Suppressor Protein p53
  • Tumor Suppressor Proteins
  • bcl-2-Associated X Protein
  • p73 protein, human
  • Cerulenin
  • Fatty Acid Synthases
  • CASP3 protein, human
  • CASP9 protein, human
  • Caspase 3
  • Caspase 9
  • Caspases