Endogenous decoy receptor 3 blocks the growth inhibition signals mediated by Fas ligand in human pancreatic adenocarcinoma

Shoichiro Tsuji, Ryo Hosotani, Shin Yonehara, Toshihiko Masui, Sidhartha S. Tulachan, Sanae Nakajima, Hiroyuki Kobayashi, Masayuki Koizumi, Eiji Toyoda, Daisuke Ito, Kazuhiro Kami, Tomohiko Mori, Koji Fujimoto, Ryuichiro Doi, Masayuki Imamura

Research output: Contribution to journalArticle

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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 anti-body (CH-11) to various extents, without Fas upregulation, when exposed to CH-11 for 48 hr after pretreatment with IFNγ. 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 IFNγ. 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.

Original languageEnglish
Pages (from-to)17-25
Number of pages9
JournalInternational Journal of Cancer
Volume106
Issue number1
DOIs
Publication statusPublished - 10-08-2003

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Fas Ligand Protein
Pancreatic Neoplasms
Adenocarcinoma
Growth
Cell Line
Membranes
Apoptosis
Neoplasms
Messenger RNA
Jurkat Cells
Tumor Necrosis Factor Receptors
Veins
Lymphoma
Proteins
Up-Regulation
Western Blotting
Regression Analysis
Polymerase Chain Reaction
4-dimethylamino-3',4'-dimethoxychalcone

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

Tsuji, Shoichiro ; Hosotani, Ryo ; Yonehara, Shin ; Masui, Toshihiko ; Tulachan, Sidhartha S. ; Nakajima, Sanae ; Kobayashi, Hiroyuki ; Koizumi, Masayuki ; Toyoda, Eiji ; Ito, Daisuke ; Kami, Kazuhiro ; Mori, Tomohiko ; Fujimoto, Koji ; Doi, Ryuichiro ; Imamura, Masayuki. / Endogenous decoy receptor 3 blocks the growth inhibition signals mediated by Fas ligand in human pancreatic adenocarcinoma. In: International Journal of Cancer. 2003 ; Vol. 106, No. 1. pp. 17-25.
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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 anti-body (CH-11) to various extents, without Fas upregulation, when exposed to CH-11 for 48 hr after pretreatment with IFNγ. 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 IFNγ. 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.",
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Tsuji, S, Hosotani, R, Yonehara, S, Masui, T, Tulachan, SS, Nakajima, S, Kobayashi, H, Koizumi, M, Toyoda, E, Ito, D, Kami, K, Mori, T, Fujimoto, K, Doi, R & Imamura, M 2003, 'Endogenous decoy receptor 3 blocks the growth inhibition signals mediated by Fas ligand in human pancreatic adenocarcinoma', International Journal of Cancer, vol. 106, no. 1, pp. 17-25. https://doi.org/10.1002/ijc.11170

Endogenous decoy receptor 3 blocks the growth inhibition signals mediated by Fas ligand in human pancreatic adenocarcinoma. / Tsuji, Shoichiro; Hosotani, Ryo; Yonehara, Shin; Masui, Toshihiko; Tulachan, Sidhartha S.; Nakajima, Sanae; Kobayashi, Hiroyuki; Koizumi, Masayuki; Toyoda, Eiji; Ito, Daisuke; Kami, Kazuhiro; Mori, Tomohiko; Fujimoto, Koji; Doi, Ryuichiro; Imamura, Masayuki.

In: International Journal of Cancer, Vol. 106, No. 1, 10.08.2003, p. 17-25.

Research output: Contribution to journalArticle

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T1 - Endogenous decoy receptor 3 blocks the growth inhibition signals mediated by Fas ligand in human pancreatic adenocarcinoma

AU - Tsuji, Shoichiro

AU - Hosotani, Ryo

AU - Yonehara, Shin

AU - Masui, Toshihiko

AU - Tulachan, Sidhartha S.

AU - Nakajima, Sanae

AU - Kobayashi, Hiroyuki

AU - Koizumi, Masayuki

AU - Toyoda, Eiji

AU - Ito, Daisuke

AU - Kami, Kazuhiro

AU - Mori, Tomohiko

AU - Fujimoto, Koji

AU - Doi, Ryuichiro

AU - Imamura, Masayuki

PY - 2003/8/10

Y1 - 2003/8/10

N2 - 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 anti-body (CH-11) to various extents, without Fas upregulation, when exposed to CH-11 for 48 hr after pretreatment with IFNγ. 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 IFNγ. 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.

AB - 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 anti-body (CH-11) to various extents, without Fas upregulation, when exposed to CH-11 for 48 hr after pretreatment with IFNγ. 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 IFNγ. 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.

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