Pancreas, 2001, Vol.23(1), pp.72-79
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.
Adenocarcinoma–Chemistry ; Antimetabolites, Antineoplastic–Pathology ; Apoptosis–Pharmacology ; Apoptosis Regulatory Proteins–Drug Effects ; Arabidopsis Proteins–Physiology ; Blotting, Western–Analysis ; Caspase 3–Analogs & Derivatives ; Caspases–Pharmacology ; Computer Systems–Analysis ; Deoxycytidine–Chemistry ; Fas Ligand Protein–Pathology ; Fatty Acid Desaturases–Chemistry ; Flow Cytometry–Pathology ; Gpi-Linked Proteins–Analysis ; Hela Cells–Pharmacology ; Humans–Physiology ; Jurkat Cells–Analysis ; Membrane Glycoproteins–Chemistry ; Neoplasm Proteins–Pathology ; Pancreatic Neoplasms–Analysis ; Proto-Oncogene Proteins–Analysis ; Proto-Oncogene Proteins C-Bcl-2–Analysis ; Receptors, Cell Surface–Analysis ; Receptors, Tnf-Related Apoptosis-Inducing Ligand–Pharmacology ; Receptors, Tumor Necrosis Factor–Chemistry ; Receptors, Tumor Necrosis Factor, Member 10c–Drug Effects ; Receptors, Tumor Necrosis Factor, Member 6b–Pathology ; Recombinant Proteins–Analysis ; Reverse Transcriptase Polymerase Chain Reaction–Pharmacology ; Tnf-Related Apoptosis-Inducing Ligand–Physiology ; Tumor Cells, Cultured–Analysis ; Tumor Necrosis Factor Decoy Receptors–Analysis ; Tumor Necrosis Factor-Alpha–Analysis ; Bcl-2-Associated X Protein–Analysis ; Bcl-X Protein–Analysis ; Fas Receptor–Analysis ; Antimetabolites, Antineoplastic ; Apoptosis Regulatory Proteins ; Arabidopsis Proteins ; Bax Protein, Human ; Bcl2l1 Protein, Human ; Faslg Protein, Human ; Fas Ligand Protein ; Gpi-Linked Proteins ; Membrane Glycoproteins ; Neoplasm Proteins ; Proto-Oncogene Proteins ; Proto-Oncogene Proteins C-Bcl-2 ; Receptors, Cell Surface ; Receptors, Tnf-Related Apoptosis-Inducing Ligand ; Receptors, Tumor Necrosis Factor ; Receptors, Tumor Necrosis Factor, Member 10c ; Receptors, Tumor Necrosis Factor, Member 6b ; Recombinant Proteins ; Tnf-Related Apoptosis-Inducing Ligand ; Tnfrsf10a Protein, Human ; Tnfrsf10b Protein, Human ; Tnfrsf10c Protein, Human ; Tnfrsf6b Protein, Human ; Tnfsf10 Protein, Human ; Tumor Necrosis Factor Decoy Receptors ; Tumor Necrosis Factor-Alpha ; Bcl-2-Associated X Protein ; Bcl-X Protein ; Fas Receptor ; Deoxycytidine ; Gemcitabine ; Fatty Acid Desaturases ; Fad7 Protein, Arabidopsis ; Casp3 Protein, Human ; Caspase 3 ; Caspases;
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