Human pancreatic cancer cells disable function of Fas receptors at several levels in Fas signal transduction pathway.
The aims of this study were to evaluate the functional expression of Fas receptors (Fas) in human pancreatic cancer cell lines; Capan-1, AsPC-1, BxPC-3, PANC-1, and MIA PaCa-2 and to search for the mechanisms of receptor-mediated inhibition of Fas signaling in these cells. Despite the expression of Fas receptors at considerable levels, exposure of these cells to agonistic Fas antibodies (500 ng/ml) induced only minimal apoptosis in 4 cell lines. The mechanisms allowing resistance to Fas-mediated apoptosis are complex. Using RT-PCR, we identified molecules which might counteract the apoptogenic signal at several levels of Fas signal transduction pathway. The most striking findings were the overexpression of Fas decoy receptors (DcR3), Fas associated phosphatase-1 (FAP-1), and FLICE-inhibitory protein (c-FLIP) in the resistant cell lines as well as in pancreatic cancer surgical specimens. In conclusion, pancreatic cancer cells express three molecules that can abrogate Fas function at different levels of Fas signaling cascade, resulting in resistance to Fas-mediated apoptosis, and this may promote the progression of this malignancy.
Elnemr
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Department of Surgery II, School of Medicine, Kanazawa University, Takara-machi 13-1, Kanazawa 920-0934, Japan. aymann1@yahoo.com
Ohta
T
T
Yachie
A
A
Kayahara
M
M
Kitagawa
H
H
Fujimura
T
T
Ninomiya
I
I
Fushida
S
S
Nishimura
G I
GI
Shimizu
K
K
Miwa
K
K
D000230:Adenocarcinoma / Q000378:metabolism*; D017209:Apoptosis / Q000502:physiology*; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D002352:Carrier Proteins / Q000378:metabolism; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D009363:Neoplasm Proteins / Q000378:metabolism*; D010190:Pancreatic Neoplasms / Q000378:metabolism*; D054645:Protein Phosphatase 1; D054595:Protein Tyrosine Phosphatase, Non-Receptor Type 13; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D014407:Tumor Cells, Cultured; D019014:fas Receptor / Q000378:metabolism*
D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; C506386:CFLAR protein, human; D002352:Carrier Proteins; D047908:Intracellular Signaling Peptides and Proteins; D009363:Neoplasm Proteins; D012333:RNA, Messenger; D019014:fas Receptor; D054645:Protein Phosphatase 1; C516742:PTPN13 protein, human; D054595:Protein Tyrosine Phosphatase, Non-Receptor Type 13; D017027:Protein Tyrosine Phosphatases; C505530:CASP8 protein, human; C506433:CASP9 protein, human; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases