Acquired resistance to Fas/CD95 ligation in U937 cells is associated with multiple molecular mechanisms.
BACKGROUND
Acquired resistance to apoptosis is a critical event in tumour development and in insensitivity toward therapy. To investigate resistance mechanisms to Fas/CD95/Apo-1-induced apoptosis, a Fas ligand-resistant variant of the U937 cell line was generated.


RESULTS
Selection for Fas resistance resulted in a partial cross-resistance to TRAIL and TNF-alpha. Activation of caspase-8 was found to be impaired and the expression of Fas was reduced. However, FADD expression and ligand-induced aggregation of Fas was intact. Inhibition of various signalling pathways with pharmacological inhibitors revealed that resistance to death receptor-mediated apoptosis was dependent on altered tyrosine phosphatase/kinase activities and de novo protein synthesis. Moreover, FLIP, an anti-apoptotic protein, was expressed to a higher extent in the resistant cells.


CONCLUSIONS
We provide evidence that acquired resistance to Fas-induced apoptosis in U937 cells involves a discrete set of molecular mechanisms which also render the cells cross-resistant to other death ligands.
Department of Molecular Biology, Umeå University, S-90187 Umeå, Sweden.
Jeanette
J
Blomberg
Kristina
K
Ruuth
Daniel
D
Santos
Erik
E
Lundgren
D017209:Apoptosis / Q000187:drug effects; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein / Q000378:metabolism; D053181:Caspase 8 / Q000378:metabolism*; D019008:Drug Resistance, Neoplasm; D004789:Enzyme Activation; D053222:Fas Ligand Protein / Q000378:metabolism; D053200:Fas-Associated Death Domain Protein / Q000494:pharmacology; D006801:Humans; D015398:Signal Transduction / Q000187:drug effects; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D020298:U937 Cells; D019014:fas Receptor / Q000494:pharmacology*
D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D053222:Fas Ligand Protein; D053200:Fas-Associated Death Domain Protein; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D014409:Tumor Necrosis Factor-alpha; D019014:fas Receptor; D053181:Caspase 8