Abstract
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-κB. Inhibition of protein kinase C by Gö6983 sensitized these cells to apoptotic challenges and strongly diminished activation of NF-κB by anti-CD95 and TRAIL. Similarly, inhibition of NF-κB by MG132 or by transient transfection with a dominant negative mutant of IκBα 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-κB 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 ΔΨm and Cytochrome c release as well as by induction of NF-κB.
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Abbreviations
- EMSA:
-
electrophoretic mobility shift assay
- FACS:
-
fluorescence activated cell sorting
- FADD:
-
Fas-associated death domain protein
- IAP:
-
inhibitor of apoptosis
- IκB:
-
inhibitory κB
- mab:
-
monoclonal antibody
- NF-κB:
-
nuclear factor -κB
- PARP:
-
poly(ADP-ribose) polymerase
- PKC:
-
protein kinase C
- PMA:
-
phorbol 12-myristate 13-acetate
- PVDF:
-
polyvinylidene difluoride
- TRAIL-R:
-
tumour necrosis factor-related apoptosis inducing ligand-receptor.
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Acknowledgements
This work was written in memory of the late Dr Daniel Szöllösi. We thank Jörg Wittlieb and Ellen Scheidhauer for excellent technical assistance, Alexandra Pries for help in editing the manuscript and Immunex Inc., Seattle, USA for supporting us with antibodies against TRAIL-receptors. This work was supported by DFG-grant (SFB415/A3) given to H Kalthoff. Some of the data are part of the doctoral thesis of H Werman, S Oestern and E Lampe.
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Trauzold, A., Wermann, H., Arlt, A. et al. CD95 and TRAIL receptor-mediated activation of protein kinase C and NF-κB contributes to apoptosis resistance in ductal pancreatic adenocarcinoma cells. Oncogene 20, 4258–4269 (2001). https://doi.org/10.1038/sj.onc.1204559
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DOI: https://doi.org/10.1038/sj.onc.1204559
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