Pancreatic adenocarcinoma cell lines show variable susceptibility to TRAIL-mediated cell death

Saleh M. Ibrahim, Jorg Ringel, Christian Schmidt, Bruno Ringel, Petra Muller, Dirk Koczan, Hans Jurgen Thiesen, Matthias Lohr

Research output: Contribution to journalArticlepeer-review

80 Scopus citations

Abstract

Background and Aims: Programmed cell death via the Fas receptor/Fas Ligand and DR4, DR5/TRAIL plays a major role in tumor escape and elimination mechanisms. It also promises to be an effective therapy alternative for aggressive tumors, as has been recently shown for colon, breast, and lung cancer cells. We attempted to clarify the role of these molecules in aggressivity of pancreatic carcinomas and to identify possible pathways as targets for therapy. Methods: Five pancreatic cell lines were investigated for the expression of FasL/Fas, DcR3, DR4, DR5/TRAIL, DcR1, DcR2, and other death pathways related molecules such as Bax, bcl-xL, bcl-2, FADD, and caspase-3 by flow cytometry, immunoblotting, and RT/PCR, both semiquantitative and real time (TaqMan). The susceptibility of these cell lines to apoptosis mediated by recombinant TRAIL was investigated. The effect of therapeutic agents (gemcitabine) on their susceptibility to TRAIL induced apoptosis was studied as well. Results: Pancreatic adenocarcinomas expressed high levels of apoptosis-inducing receptors and ligands, They showed differential susceptibility to cell death induced by TRAIL, despite expressing intact receptors and signaling machineries. Treatment with commonly used therapeutic agents did not augment their susceptibility to apoptosis. This could be explained by the fact that they expressed differentially high levels of decoy receptors, as well as molecules known as inhibitors of apoptosis. Conclusions: The data suggest that pancreatic carcinoma cells have developed different mechanisms to evade the immune system. One is the expression of nonfunctional receptors, decoy receptors, and molecules that block cell death, such as bcl2 and bcl-xL. The second is the expression of apoptosis-inducing ligands, such as TRAIL, that could induce cell death of immune cells. The success in treating malignant tumors by recombinant TRAIL might apply to some but not all pancreatic tumors because of their differential resistance to TRAIL-induced cell death.

Original languageBritish English
Pages (from-to)72-79
Number of pages8
JournalPancreas
Volume23
Issue number1
DOIs
StatePublished - 2001

Keywords

  • Apoptosis
  • Chemotherapy
  • FasL
  • Pancreatic carcinoma
  • TRAIL

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