The differential sensitivity of Bc1-2-overexpressing human breast tumor cells to TRAIL or doxorubicin-induced apoptosis is dependent on Bc1-2 protein levels

Oncogene. 2001 Oct 25;20(48):7128-33. doi: 10.1038/sj.onc.1204887.

Abstract

Bc1-2 protein is a potent anti-apoptotic protein that inhibits a mitochondria-operated pathway of apoptosis in many cells. DNA damaging agents and death receptor ligands can activate this mitochondrial apoptotic mechanism. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has been suggested to escape from the inhibitory action of Bc1-2 protein. We show that in human breast tumor MCF-7 cells, TRAIL induced a mitochondrial pathway of apoptosis that involved cytochrome c release from mitochondria and activation of caspase 9. The DNA damaging drug doxorubicin also activated this mitochondria-regulated mechanism of apoptosis, which was inhibited in Bc1-2-overexpressing cells. We also demonstrate that in MCF-7 cells Bc1-2 might confer resistance to TRAIL-induced apoptosis, depending on the expression levels of the anti-apoptotic protein. These results indicate that enhanced expression of Bc1-2 in tumor cells can render these cells less sensitive not only to chemotherapeutic drugs but also to TRAIL.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma / genetics
  • Adenocarcinoma / metabolism
  • Adenocarcinoma / pathology*
  • Antibiotics, Antineoplastic / pharmacology*
  • Antineoplastic Agents / pharmacology*
  • Apoptosis / drug effects*
  • Apoptosis Regulatory Proteins
  • Breast Neoplasms / genetics
  • Breast Neoplasms / metabolism
  • Breast Neoplasms / pathology*
  • Caspase 9
  • Caspases / metabolism
  • Cytochrome c Group / metabolism
  • DNA Damage
  • DNA, Neoplasm / drug effects
  • DNA, Neoplasm / genetics
  • Doxorubicin / pharmacology*
  • Drug Resistance, Neoplasm / physiology*
  • Enzyme Activation / drug effects
  • Female
  • Humans
  • Membrane Glycoproteins / pharmacology*
  • Mitochondria / drug effects
  • Neoplasm Proteins / analysis
  • Neoplasm Proteins / physiology*
  • Protein Transport / drug effects
  • Proto-Oncogene Proteins / metabolism
  • Proto-Oncogene Proteins c-bcl-2 / physiology*
  • TNF-Related Apoptosis-Inducing Ligand
  • Tubulin / analysis
  • Tumor Cells, Cultured / drug effects
  • Tumor Cells, Cultured / pathology
  • Tumor Necrosis Factor-alpha / pharmacology*
  • bcl-2-Associated X Protein

Substances

  • Antibiotics, Antineoplastic
  • Antineoplastic Agents
  • Apoptosis Regulatory Proteins
  • Cytochrome c Group
  • DNA, Neoplasm
  • Membrane Glycoproteins
  • Neoplasm Proteins
  • Proto-Oncogene Proteins
  • Proto-Oncogene Proteins c-bcl-2
  • TNF-Related Apoptosis-Inducing Ligand
  • TNFSF10 protein, human
  • Tubulin
  • Tumor Necrosis Factor-alpha
  • bcl-2-Associated X Protein
  • Doxorubicin
  • CASP9 protein, human
  • Caspase 9
  • Caspases