CD95 and TRAIL receptor-mediated activation of protein kinase C and NF-kappaB contributes to apoptosis resistance in ductal pancreatic adenocarcinoma cells.
The molecular alterations in tumour cells leading to resistance towards apoptosis induced by CD95 and TRAIL-receptors are not fully understood. We report here that the stimulation of the CD95- and TRAIL-resistant human pancreatic adenocarcinoma cell line PancTuI with an agonistic anti-CD95 antibody or TRAIL resulted in activation of protein kinase C and NF-kappaB. Inhibition of protein kinase C by Gö6983 sensitized these cells to apoptotic challenges and strongly diminished activation of NF-kappaB by anti-CD95 and TRAIL. Similarly, inhibition of NF-kappaB by MG132 or by transient transfection with a dominant negative mutant of IkappaBalpha restored the responsiveness of PancTuI cells to both death ligands. In the CD95 and TRAIL-sensitive cell line Colo357 the induction of protein kinase C and NF-kappaB following activation of CD95 and TRAIL-R was very moderate compared with PancTuI cells. However, pre-incubation of these cells with PMA strongly reduced their apoptotic response to anti-CD95 and TRAIL. Taken together, we show that activation of protein kinase C operates directly in a death receptor-dependent manner in PancTuI cells and protect pancreatic tumour cells from anti-CD95 and TRAIL-mediated apoptosis by preventing the loss DeltaPsim and Cytochrome c release as well as by induction of NF-kappaB.
Trauzold
A
A
Molecular Oncology, Clinic for General Surgery, Christian-Albrechts-University, Kiel, Germany.
Wermann
H
H
Arlt
A
A
Schütze
S
S
Schäfer
H
H
Oestern
S
S
Röder
C
C
Ungefroren
H
H
Lampe
E
E
Heinrich
M
M
Walczak
H
H
Kalthoff
H
H
D000230:Adenocarcinoma / Q000201:enzymology / Q000378:metabolism / Q000473:pathology*; D017209:Apoptosis / Q000502:physiology*; D051017:Apoptosis Regulatory Proteins; D004789:Enzyme Activation; D006801:Humans; D008562:Membrane Glycoproteins / Q000502:physiology*; D016328:NF-kappa B / Q000378:metabolism*; D010190:Pancreatic Neoplasms / Q000201:enzymology / Q000378:metabolism / Q000473:pathology*; D011493:Protein Kinase C / Q000378:metabolism*; D053221:TNF-Related Apoptosis-Inducing Ligand; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology*; D019014:fas Receptor / Q000502:physiology*
D051017:Apoptosis Regulatory Proteins; D008562:Membrane Glycoproteins; D016328:NF-kappa B; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D014409:Tumor Necrosis Factor-alpha; D019014:fas Receptor; D011493:Protein Kinase C