Bcl-x and Bcl-2 inhibit TNF and Fas-induced apoptosis and activation of phospholipase A2 in breast carcinoma cells

Oncogene. 1995 Jun 15;10(12):2297-305.


Tumor necrosis factor (TNF) induces cel death in several tumor cell lines by undefined mechanisms. Using a cDNA expression cloning strategy we identified two cDNAs that completely inhibit the TNF-induced death pathway in MCF7 breast carcinoma cells. These cDNAs encoded for Bcl-2 and Bcl-x. To compare the cytotoxic signal transduction pathway induced by the TNF receptor versus that induced by Fas, we transfected MCF7 cells with a Fas expression construct. The resulting cell line, MCF-Fas, was highly sensitive to cytotoxicity induced by TNF or anti-Fas. Expression of either bcl-2 or bcl-x in these cells rendered them completely resistant to lysis induced by either TNF or Fas. Interestingly, exposure of MCF-Fas cells to anti-Fas or TNF induced activation of phospholipase A2 (PLA2), while only TNF activated NF-kappa B. Activation of PLA2 was completely blocked whereas activation of NF-kappa B was unaffected by overexpression of either bcl-x or bcl-2. Moreover, PLA2-inhibitors, quinacrine and dexamethasone, partially inhibited cytotoxicity induced by either TNF or anti-Fas. These data suggest an involvement of PLA2 in both TNF- and Fas-mediated cytotoxicity and a novel mechanism of action for bcl-2 and bcl-x, i.e. inhibition of arachidonic acid metabolism, by which they may, in addition of apoptosis, modulate inflammation.

Publication types

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

MeSH terms

  • Antigens, Surface / genetics
  • Antigens, Surface / metabolism*
  • Apoptosis* / genetics
  • Apoptosis* / physiology
  • Base Sequence
  • Breast Neoplasms / enzymology
  • Breast Neoplasms / genetics
  • Breast Neoplasms / metabolism*
  • Breast Neoplasms / pathology
  • Cell Division / drug effects
  • Ceramides / metabolism
  • Dexamethasone / pharmacology
  • Drug Resistance / genetics
  • Enzyme Activation / drug effects
  • Female
  • Humans
  • Luciferases / biosynthesis
  • Molecular Sequence Data
  • NF-kappa B / drug effects
  • NF-kappa B / metabolism*
  • Phospholipases A / biosynthesis*
  • Phospholipases A2
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / metabolism*
  • Proto-Oncogene Proteins c-bcl-2
  • Quinacrine / pharmacology
  • Signal Transduction
  • Sphingomyelin Phosphodiesterase / pharmacology
  • Sphingosine / analogs & derivatives
  • Sphingosine / pharmacology
  • Tumor Cells, Cultured
  • Tumor Necrosis Factor-alpha / antagonists & inhibitors*
  • bcl-X Protein
  • fas Receptor


  • Antigens, Surface
  • BCL2L1 protein, human
  • Ceramides
  • N-acetylsphingosine
  • NF-kappa B
  • Proto-Oncogene Proteins
  • Proto-Oncogene Proteins c-bcl-2
  • Tumor Necrosis Factor-alpha
  • bcl-X Protein
  • fas Receptor
  • Dexamethasone
  • Luciferases
  • Phospholipases A
  • Phospholipases A2
  • Sphingomyelin Phosphodiesterase
  • Quinacrine
  • Sphingosine