Bcl-2 inhibits calcineurin-mediated Fas ligand expression in antitumor drug-treated baby hamster kidney cells

Jpn J Cancer Res. 2000 Jul;91(7):706-14. doi: 10.1111/j.1349-7006.2000.tb01003.x.

Abstract

It is well known that human leukemia cells, such as HL-60 and U937 are sensitive to antitumor drugs, but human normal lung fibroblasts, such as WI-38 cells are resistant to the drugs. However, the mechanisms of the different responses to apoptosis in these cell lines remain unclear. We report here that an increase of Fas and Fas ligand (FasL) expression was required for antitumor drug-induced apoptosis in WI-38 and baby hamster kidney (BHK) cells, but not in HL-60 cells. Then, we used BHK cells transfected with the bcl-2 gene to investigate the involvement of complex formation of Bcl-2 and calcineurin. Calcineurin was imported to the nucleus in response to the drug treatment. Overexpression of Bcl-2 and cyclosporin A treatment inhibited the nuclear import and FasL expression, and as a result, both inhibited apoptosis. Although a caspase inhibitor, z-Asp-CH2-DCB, suppressed the drug-induced apoptosis, it failed to inhibit the drug-induced expression of Fas and FasL. These findings suggest that initially the Fas / FasL system is activated by calcineurin-dependent transcription followed by activation of the downstream caspase cascade resulting in antitumor drug-induced apoptosis in BHK cells, but not in HL-60 cells. Furthermore, Bcl-2 inhibits the nuclear import of calcineurin and suppresses calcineurin-mediated FasL expression during antitumor drug-induced apoptosis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology*
  • Apoptosis / drug effects
  • Apoptosis / physiology
  • Aspartic Acid / analogs & derivatives*
  • Aspartic Acid / pharmacology
  • Calcineurin / metabolism
  • Calcineurin Inhibitors*
  • Caspases / metabolism
  • Cells, Cultured
  • Cricetinae
  • Cyclosporine / pharmacology
  • Drug Resistance, Neoplasm / physiology
  • Enzyme Activation
  • Fas Ligand Protein
  • Fibroblasts / drug effects
  • HL-60 Cells / drug effects
  • Humans
  • Kidney / drug effects
  • Kidney / metabolism
  • Kidney / physiology*
  • Lung / cytology
  • Lung / drug effects
  • Membrane Glycoproteins / antagonists & inhibitors*
  • Membrane Glycoproteins / biosynthesis
  • Membrane Glycoproteins / physiology
  • Protease Inhibitors / pharmacology
  • Proto-Oncogene Proteins c-bcl-2 / genetics
  • Proto-Oncogene Proteins c-bcl-2 / physiology*
  • Pyrones / pharmacology
  • Transfection
  • Up-Regulation / physiology
  • fas Receptor / physiology

Substances

  • Antineoplastic Agents
  • Calcineurin Inhibitors
  • FASLG protein, human
  • Fas Ligand Protein
  • Membrane Glycoproteins
  • Protease Inhibitors
  • Proto-Oncogene Proteins c-bcl-2
  • Pyrones
  • benzyloxycarbonyl-Asp-CH2OC(O)-2,6-dichlorobenzene
  • fas Receptor
  • pironetin
  • Aspartic Acid
  • Cyclosporine
  • Calcineurin
  • Caspases