Apoptosis in the absence of caspase 3

Oncogene. 2001 Oct 4;20(45):6570-8. doi: 10.1038/sj.onc.1204815.


MCF-7 human breast cancer cells do not express caspase 3, thought by some to be a critical component of the apoptosis cascade. Nonetheless, both mock- and bcl-2-transfected MCF-7 cells undergo apoptosis after treatment with a variety of stimuli, including the DNA-cleaving antimitotic agent, neocarzinostatin (NCS). Transfection with bcl-2 shifts the concentration-response curve to NCS but does not change the phenomenology of apoptosis when it occurs. In both cases, NCS treatment results in condensation and fragmentation of MCF-7 cell nuclei and release of cytochrome c from the mitochondria to the cytosol. This apoptosis is accompanied by decreased levels of Bcl-2 and increased levels of Bax. Using a series of caspase inhibitors with overlapping specificities, enzyme-specific chromogenic substrates, and an antibody specific for activated caspase 7, we have determined that apoptosis in MCF-7 cells proceeds via sequential activation of caspases 9, 7 and 6. P21 is detected only after activation of caspase 7, and P53 is neither expressed at baseline nor up-regulated with apoptosis induction. This pathway bypasses the need for activated caspase 3 in these cells.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Antibiotics, Antineoplastic / pharmacology
  • Apoptosis*
  • Breast Neoplasms / enzymology*
  • Breast Neoplasms / metabolism
  • Breast Neoplasms / pathology*
  • Caspase 3
  • Caspase Inhibitors
  • Caspases / metabolism
  • Caspases / physiology*
  • Cyclin-Dependent Kinase Inhibitor p21
  • Cyclins / metabolism
  • Cysteine Proteinase Inhibitors / pharmacology
  • Cytochrome c Group / metabolism
  • Humans
  • Kinetics
  • Models, Biological
  • Proto-Oncogene Proteins / metabolism
  • Proto-Oncogene Proteins c-bcl-2 / genetics
  • Proto-Oncogene Proteins c-bcl-2 / metabolism
  • Transfection
  • Tumor Cells, Cultured
  • Tumor Suppressor Protein p53 / metabolism
  • Zinostatin / pharmacology
  • bcl-2-Associated X Protein


  • Antibiotics, Antineoplastic
  • BAX protein, human
  • CDKN1A protein, human
  • Caspase Inhibitors
  • Cyclin-Dependent Kinase Inhibitor p21
  • Cyclins
  • Cysteine Proteinase Inhibitors
  • Cytochrome c Group
  • Proto-Oncogene Proteins
  • Proto-Oncogene Proteins c-bcl-2
  • Tumor Suppressor Protein p53
  • bcl-2-Associated X Protein
  • Zinostatin
  • CASP3 protein, human
  • Caspase 3
  • Caspases