title: Endogenous decoy receptor 3 blocks the growth inhibition signals mediated by Fas ligand in human pancreatic adenocarcinoma.
abstract: 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.
authors.affiliation: Department of Surgery and Surgical Basic Science, Graduate School of Medicine, Kyoto University, Kyoto, Japan. stuji@kuhp.kyoto-u.ac.jp
authors.forename: Shoichiro
authors.initials: S
authors.lastname: Tsuji
authors.forename: Ryo
authors.initials: R
authors.lastname: Hosotani
authors.forename: Shin
authors.initials: S
authors.lastname: Yonehara
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Masui
authors.forename: Sidhartha S
authors.initials: SS
authors.lastname: Tulachan
authors.forename: Sanae
authors.initials: S
authors.lastname: Nakajima
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Kobayashi
authors.forename: Masayuki
authors.initials: M
authors.lastname: Koizumi
authors.forename: Eiji
authors.initials: E
authors.lastname: Toyoda
authors.forename: Daisuke
authors.initials: D
authors.lastname: Ito
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Kami
authors.forename: Tomohiko
authors.initials: T
authors.lastname: Mori
authors.forename: Koji
authors.initials: K
authors.lastname: Fujimoto
authors.forename: Ryuichiro
authors.initials: R
authors.lastname: Doi
authors.forename: Masayuki
authors.initials: M
authors.lastname: Imamura
mesh_terms: 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
chemical_list: 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