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

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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

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

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    Tsuji, S., Hosotani, R., Yonehara, S., Masui, T., Tulachan, S. S., 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, 106(1), 17-25. https://doi.org/10.1002/ijc.11170