Susceptibility to drug-induced apoptosis correlates with differential modulation of Bad, Bcl-2 and Bcl-xL protein levels

Cell Death Differ. 2000 Jun;7(6):574-86. doi: 10.1038/sj.cdd.4400688.

Abstract

To define the responses of apoptotic regulatory proteins to different chemotherapeutic agents, we investigated the expression of Bcl-2 family gene products, the release of cytochrome c, and the activation of pro-caspase-3 during apoptosis induced by Taxol and Thiotepa, in the MCF-7 breast carcinoma and the HL-60 leukemia cell lines. The earliest event induced by drug exposure was increase in Bad protein levels, followed by Bcl-2 down-regulation, cytochrome c release, and Bcl-xL and Bax up-regulation. Bak accumulation was a late event. Activation of pro-caspase-3 and cleavage of Bcl-2 protein occurred in the HL-60 cells only, and followed the cytochrome c release. The overall responses were qualitatively similar in both cell types, but MCF-7 cells treated with Taxol showed a significant delay in apoptosis, correlating with early up-regulation of Bcl-2 and delayed release of cytochrome c. We conclude that Bad up-regulation is an early indicator of a cellular response that will lead to cell death, but may be modulated by survival mechanisms, which cumulatively govern the ultimate susceptibility to apoptosis.

Publication types

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

MeSH terms

  • 14-3-3 Proteins
  • Apoptosis / drug effects*
  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism*
  • Caspase 3
  • Caspases / genetics
  • Cell Survival / drug effects
  • Cytochrome c Group / metabolism
  • Enzyme Precursors / genetics
  • Gene Expression
  • HL-60 Cells
  • Humans
  • Membrane Proteins / genetics
  • Paclitaxel / pharmacology*
  • Proteins / genetics
  • Proto-Oncogene Proteins c-bcl-2 / genetics
  • Proto-Oncogene Proteins c-bcl-2 / metabolism*
  • Thiotepa / pharmacology*
  • Tumor Cells, Cultured
  • Tyrosine 3-Monooxygenase*
  • bcl-2 Homologous Antagonist-Killer Protein
  • bcl-Associated Death Protein
  • bcl-X Protein

Substances

  • 14-3-3 Proteins
  • BAD protein, human
  • BAK1 protein, human
  • BCL2L1 protein, human
  • Carrier Proteins
  • Cytochrome c Group
  • Enzyme Precursors
  • Membrane Proteins
  • Proteins
  • Proto-Oncogene Proteins c-bcl-2
  • bcl-2 Homologous Antagonist-Killer Protein
  • bcl-Associated Death Protein
  • bcl-X Protein
  • Thiotepa
  • Tyrosine 3-Monooxygenase
  • CASP3 protein, human
  • Caspase 3
  • Caspases
  • Paclitaxel