Endogenous decoy receptor 3 blocks the growth inhibition signals mediated by Fas ligand in human pancreatic adenocarcinoma.
Many cancers are resistant to Fas-mediated apoptosis despite the expression of Fas. To investigate the mechanisms by which Fas signals are attenuated, we focused on decoy receptor 3 (DcR3). DcR3 is a soluble receptor against Fas ligand belonging to the tumor necrosis factor receptor superfamily and overexpresses in some forms of cancers. Exogenous DcR3 inhibits Fas-mediated apoptosis in Fas-sensitive Jurkat cells. In our study, we examined the expression and function of DcR3 in pancreatic cancers. TaqMan RT-PCR showed that DcR3 mRNA was highly expressed in pancreatic cancer cell lines (71%) and tissues (67%). Its expression significantly correlated with cancer invasion to veins. Western blotting showed that the DcR3 protein was produced and secreted in 4 of 6 cell lines. The protein expressions were compatible with the mRNA expression. Five of 7 pancreatic cancer cell lines became sensitive to agonistic anti-Fas antibody (CH-11) to various extents, without Fas upregulation, when exposed to CH-11 for 48 hr after pretreatment with IFNgamma. Four of 7 pancreatic cancer cell lines were inhibited from growing, compared to control cells, when cocultured with membrane-bounded Fas ligand (mFasL) transfected lymphomas for 48 hr after pretreatment with IFNgamma. DcR3 reduced this growth inhibition when added exogenously. Regression analysis showed that the DcR3 expression significantly correlated with the sensitivity to mFasL, and not to CH-11. These results suggest that DcR3 is highly expressed in many pancreatic cancers and endogenous DcR3 blocks the growth inhibition signals mediated by mFasL. DcR3 can be a candidate target molecule for the therapeutic intervention.
Tsuji
Shoichiro
S
Department of Surgery and Surgical Basic Science, Graduate School of Medicine, Kyoto University, Kyoto, Japan. stuji@kuhp.kyoto-u.ac.jp
Hosotani
Ryo
R
Yonehara
Shin
S
Masui
Toshihiko
T
Tulachan
Sidhartha S
SS
Nakajima
Sanae
S
Kobayashi
Hiroyuki
H
Koizumi
Masayuki
M
Toyoda
Eiji
E
Ito
Daisuke
D
Kami
Kazuhiro
K
Mori
Tomohiko
T
Fujimoto
Koji
K
Doi
Ryuichiro
R
Imamura
Masayuki
M
D000230:Adenocarcinoma / Q000378:metabolism* / Q000473:pathology; D017209:Apoptosis; D015153:Blotting, Western; D002455:Cell Division; D018920:Coculture Techniques; D053222:Fas Ligand Protein; D005819:Genetic Markers; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000378:metabolism*; D010190:Pancreatic Neoplasms / Q000378:metabolism* / Q000473:pathology; D012333:RNA, Messenger / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000378:metabolism*; D018124:Receptors, Tumor Necrosis Factor; D053323:Receptors, Tumor Necrosis Factor, Member 6b; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors; D014407:Tumor Cells, Cultured; D015854:Up-Regulation; D019014:fas Receptor / Q000378:metabolism
C505661:FASLG protein, human; D053222:Fas Ligand Protein; D005819:Genetic Markers; D008562:Membrane Glycoproteins; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; D018124:Receptors, Tumor Necrosis Factor; D053323:Receptors, Tumor Necrosis Factor, Member 6b; C505911:TNFRSF6B protein, human; D019014:fas Receptor; D007371:Interferon-gamma