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CD95 and TRAIL receptor-mediated activation of protein kinase C and NF-κB contributes to apoptosis resistance in ductal pancreatic adenocarcinoma cells

Oncogene volume 20, pages 4258–4269 (2001)Cite this article

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.

References

  • Barket M, Gilmore TD . 1999 Oncogene 18: 6910–6924

  • Beg AA, Baltimore D . 1996 Science 274: 782–784

  • Bharti A, Kraeft SK, Gounder M, Pandey P, Jin S, Yuan ZM, Lees-Miller SP, Weichselbaum R, Weaver D, Chen LB, Kufe D, Kharbanda S . 1998 Mol. Cell. Biol. 18: 6719–6728

  • Chaudhary PM, Eby M, Jasmin A, Bookwalter A, Murray J, Hood L . 1997 Immunity 7: 821–830

  • Chen C-Y, Faller DV . 1999 J. Biol. Chem. 274: 15320–15328

  • Degli-Esposti MA, Dougall WC, Smolak PJ, Waugh JY, Smith CA, Goodwin RG . 1997a Immunity 7: 813–820

  • Degli-Esposti MA, Smolak PJ, Walczak H, Waugh J, Huang CP, DuBose RF, Goodwin RG, Smith CA . 1997b J. Exp. Med. 7: 1165–1170

  • Gschwendt M, Dieterich S, Rennecke J, Kittstein W, Mueller H-J, Johannes F-J . 1996 FEBS Lett. 392: 77–80

  • Hinz S, Trauzold A, Boenicke L, Sandberg C, Beckmann S, Bayer E, Walczak H, Kalthoff H, Ungefroren H . 2000 Oncogene 19: 5477–5486

  • Irmler M, Thome M, Hahne M, Schneider P, Hofmann K, Steiner V, Bodmer JL, Schroter M, Burns K, Mattmann C, Rimoldi D, French LE, Tschopp J . 1997 Nature 388: 190–195

  • Jamieson L, Carpenter L, Biden TJ, Fields AP . 1999 J. Biol. Chem. 274: 3927–3930

  • Johannes F-J, Prestle J, Dieterich S, Oberhagemann P, Link G, Pfitzenmaier K . 1995 Eur. J. Biochem. 227: 303–307

  • Johannes F-J, Horn J, Link G, Haas E, Siemienski K, Wajant H, Pfitzenmaier K . 1998 Eur. J. Biochem. 257: 47–54

  • Kobayashi D, Watanabe N, Yamauchi N, Tsuji N, Sato T, Sasaki H, Okamoto T, Niitsu Y . 1997 Chemotherapy 43: 415–423

  • Krammer PH . 1999 Adv. Immunol. 99: 163–210

  • Kumuda CD, White CW . 1997 J. Biol. Chem. 272: 14914–14920

  • Kupatt JM, Baumann B, Herr I, Wirth T, Debatin KM . 1998 Blood 91: 4624–4631

  • Leverkus M, Neumann M, Mengling T, Rauch CT, Bröcker EB, Krammer PH, Walczak H . 2000 Cancer Res. 60: 553–559

  • Malinin NL, Boldin MP, Kovalenko AV, Wallach D . 1997 Nature 385: 540–544

  • Nagata S . 1997 Cell 88: 355–365

  • Packham G, Lahti JM, Fee BE, Gawn JM, Coustan-Smith E, Campana D, Douglas I, Kidd VJ, Ghosh S, Cleveland JL . 1997 Cell Death Differ. 4: 130–139

  • Pan G, O'Rourke K, Chinnaiyan AM, Gentz R, Ebner R, Ni J, Dixit VM . 1997 Science 276: 111–113

  • Peter ME, Scaffidi C, Medema JP, Kischkel F, Krammer PH . 1998 Apoptosis, problems and diseases Springer: Heidelberg, Germany pp. 25–63

  • Pitti RM, Marsters SA, Ruppert S, Donahue CJ, Moore A, Ashkenazi A . 1996 J. Biol. Chem. 271: 12687–12690

  • Ponton A, Clement MV, Stamenkovic I . 1996 J. Biol. Chem. 271: 8991–8995

  • Ravi R, Bedi A, Fuchs EJ, Bedi A . 1998 Cancer Res. 58: 882–886

  • Rayet B, Celinas C . 1999 Oncogene 18: 6938–6947

  • Reed JC . 1998 Oncogene 17: 3225–3236

  • Sanz L, Sanchez P, Lallena MJ, Diaz-Meco MT, Moscat J . 1999 EMBO J. 18: 3044–3053

  • Sawai H, Okazaki T, Takeda Y, Tashima M, Sawada H, Okuma M, Kishi S, Umehara H, Domae N . 1997 J. Biol. Chem. 272: 2452–2458

  • Scaffidi C, Fulda S, Srinivasan A, Feng L, Friesen C, Tomaselli KJ, Debatin KM, Krammer PH, Peter M . 1998 EMBO J. 17: 1675–1687

  • Scaffidi C, Schmitz I, Zha J, Korsmeyer SJ, Krammer PH, Peter M . 1999 J. Biol. Chem. 274: 22532–22538

  • Schäfer H, Arlt A, Trauzold A, Hünermann-Jansen A, Schmidt WE . 1999 Biochem. Biophys. Res. Commun. 262: 139–145

  • Schäfer H, Diebel J, Arlt A, Trauzold A, Schmidt WE . 1998 FEBS Lett. 436: 139–143

  • Stehlik C, de Martin R, Kumbashiri I, Schmid JA, Binder BR, Lipp J . 1998 J. Exp. Med. 188: 211–216

  • Ungefroren H, Voss M, Jansen M, Roeder C, Henne-Bruns D, Kremer B, Kalthoff H . 1998 Cancer Res. 58: 1741–1749

  • von Reyher U, Sträter J, Kittstein W, Gschwendt M, Krammer P, Müller P . 1998 Cancer Res. 58: 526–534

  • Walczak H, Degli-Esposti MA, Johnson RS, Smolak PJ, Waugh JY, Boiani N, Timour MS, Gerhart MJ, Schooley KA, Smith CA, Goodwin RG, Rauch CT . 1997 EMBO J. 16: 5386–5397

  • Wang CY, Mayo MW, Korneluk RG, Goeddel DV, Baldwin AS . 1998 Science 281: 1680–1683

  • Wiley SR, Schooley K, Smolak PJ, Din WS, Huang JK, Nichol JK, Sutherland GR, Smith TD, Rauch CT, Smith GA, Goodwin RG . 1995 Immunity 3: 673–682

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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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Authors and Affiliations

  1. Molecular Oncology, Clinic for General Surgery, Christian-Albrechts-University, Kiel, Germany

    Anna Trauzold, Hendrik Wermann, Stefanie Oestern, Christian Röder, Hendrik Ungefroren, Esther Lampe & Holger Kalthoff

  2. 1st Department of Medicine, Laboratory of Molecular Gastroenterology, Christian-Albrechts-University, Kiel, Germany

    Alexander Arlt & Heiner Schäfer

  3. Institute of Immunology, Christian-Albrechts-University, Kiel, Germany

    Stefan Schütze & Michael Heinrich

  4. Department for Apoptosis Regulation, German Center for Cancer Research, Heidelberg, Germany

    Henning Walczak

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  1. Anna Trauzold
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  2. Hendrik Wermann
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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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