Bcl-x and Bcl-2 inhibit TNF and Fas-induced apoptosis and activation of phospholipase A2 in breast carcinoma cells.
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.
Jäättelä
M
M
Department of Tumor Cell Biology, Danish Cancer Society Research Center, Copenhagen.
Benedict
M
M
Tewari
M
M
Shayman
J A
JA
Dixit
V M
VM
D000954:Antigens, Surface / Q000235:genetics / Q000378:metabolism*; D017209:Apoptosis / Q000235:genetics / Q000502:physiology; D001483:Base Sequence; D001943:Breast Neoplasms / Q000201:enzymology / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002455:Cell Division / Q000187:drug effects; D002518:Ceramides / Q000378:metabolism; D003907:Dexamethasone / Q000494:pharmacology; D004351:Drug Resistance / Q000235:genetics; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D006801:Humans; D008156:Luciferases / Q000096:biosynthesis; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000187:drug effects / Q000378:metabolism*; D010741:Phospholipases A / Q000096:biosynthesis*; D054467:Phospholipases A2; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2; D011796:Quinacrine / Q000494:pharmacology; D015398:Signal Transduction; D013108:Sphingomyelin Phosphodiesterase / Q000494:pharmacology; D013110:Sphingosine / Q000031:analogs & derivatives / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors*; D051020:bcl-X Protein; D019014:fas Receptor
D000954:Antigens, Surface; C494811:BCL2L1 protein, human; D002518:Ceramides; C064769:N-acetylsphingosine; D016328:NF-kappa B; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D014409:Tumor Necrosis Factor-alpha; D051020:bcl-X Protein; D019014:fas Receptor; D003907:Dexamethasone; D008156:Luciferases; D010741:Phospholipases A; D054467:Phospholipases A2; D013108:Sphingomyelin Phosphodiesterase; D011796:Quinacrine; D013110:Sphingosine