Cathepsins and BID are involved in the molecular switch between apoptosis and autophagy in breast cancer MCF-7 cells exposed to camptothecin

J Physiol Pharmacol. 2005 Jun:56 Suppl 3:159-79.

Abstract

The details of molecular switching points between apoptosis and autophagy in tumor cells have still not been fully elucidated. This study focused on the role of cathepsin B and its substrate, BID as molecular links between apoptosis and autophagy in human breast cancer MCF-7 cells exposed to camptothecin. Apoptosis occurred rapidly with a peak in 60 min after drug administration, whereas autophagy developed at a much slower rate with continuous progression during 24 h of cell exposure to the drug. CPT induced very rapid activation of cathepsin B. Inhibition of cathepsins by E64d prevented CPT-induced BAX and BID aggregation on mitochondria and reduced significantly reduced apoptotic cell number. The above effects were accompanied by an increase in autophagosome formation, measured by expression of MAP I LC3. BID knock down resulted in strong suppression of CPT-induced apoptosis and a shift of cell death towards autophagy, manifesting with an increase of Beclin 1 and MAP I LC3 cellular content.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents, Phytogenic / pharmacology*
  • Apoptosis / drug effects*
  • Apoptosis Regulatory Proteins / metabolism
  • Autophagy / drug effects*
  • BH3 Interacting Domain Death Agonist Protein / metabolism*
  • Beclin-1
  • Breast Neoplasms / enzymology
  • Breast Neoplasms / metabolism*
  • Breast Neoplasms / ultrastructure
  • Camptothecin / pharmacology*
  • Cathepsin B / antagonists & inhibitors
  • Cathepsin B / metabolism*
  • Cell Line, Tumor
  • Cysteine Proteinase Inhibitors / pharmacology
  • Enzyme Activation
  • Female
  • Humans
  • Kinetics
  • Laser Scanning Cytometry
  • Leucine / analogs & derivatives
  • Leucine / pharmacology
  • Membrane Proteins / metabolism
  • Microscopy, Confocal
  • Microscopy, Electron, Transmission
  • Microtubule-Associated Proteins / metabolism
  • Mitochondria / drug effects
  • Mitochondria / metabolism
  • Signal Transduction / drug effects*
  • bcl-2-Associated X Protein / metabolism

Substances

  • Antineoplastic Agents, Phytogenic
  • Apoptosis Regulatory Proteins
  • BAX protein, human
  • BECN1 protein, human
  • BH3 Interacting Domain Death Agonist Protein
  • BID protein, human
  • Beclin-1
  • Cysteine Proteinase Inhibitors
  • Membrane Proteins
  • Microtubule-Associated Proteins
  • bcl-2-Associated X Protein
  • Cathepsin B
  • Leucine
  • aloxistatin
  • Camptothecin