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RESEARCH ARTICLE |
1
Research Unit Molecular Oncology, Clinic for General Surgery and Thoracic
Surgery, Christian-Albrechts-University, 24105 Kiel, Germany
2
Department of Medicine, Christian-Albrechts-University, 24105 Kiel,
Germany
*
Author for correspondence (e-mail:
hkalthoff{at}email.uni-kiel.de
)
Accepted April 23, 2001
In this study we investigated the functional role of FAP-1 as a potential inhibitor of CD95 (Fas, APO-1)-mediated apoptosis in pancreatic cancer cells. Stable transfection of the CD95-sensitive, FAP-1-negative cell line Capan-1 with an FAP-1 cDNA resulted in a strongly decreased sensitivity to CD95-induced apoptosis, as measured by DNA fragmentation and caspase-3 activity. Inhibition of cellular protein tyrosine phosphatases with orthovanadate dose-dependently increased CD95-induced apoptosis in CD95-resistant FAP-1-positive Panc89 and Capan-1-FAP-1 cells almost to the level seen in wild-type Capan-1 cells. Blocking the CD95/FAP-1 interaction in Panc89 cells by cytoplasmic microinjection of a synthetic tripeptide mimicking the C terminus of CD95 resulted in a mean 5.5-fold increase in apoptosis compared to cells that received a control peptide. Using confocal laser scanning microscopy we show that in Panc89 cells FAP-1 is mainly associated with the Golgi complex and with peripheral vesicles. FAP-1 displayed enhanced colocalization with CD95 upon CD95 stimulation in the Golgi complex but not in surface-associated vesicles. This correlated with a decrease in plasma membrane staining for CD95 as determined by FACS analysis. Inhibition of Golgi anterograde transport by brefeldin A abolished the anti-CD95-induced colocalization of FAP-1 and CD95 as well as the decrease in cell-surface-associated CD95. Finally, we demonstrate by immunohistochemistry that FAP-1 is strongly expressed in tumor cells from pancreatic carcinoma tissues. Taken together, these results show that FAP-1 can protect pancreatic carcinoma cells from CD95-mediated apoptosis, probably by preventing anti-CD95-induced translocation of CD95 from intracellular stores to the cell surface.
Key words: CD95-induced cell death, Pancreatic cancer, Human, Immune escape
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