Overexpression of indoleamine 2,3-dioxygenase in human endometrial carcinoma cells induces rapidtumor growth in a mouse xenograft model

Norio Yoshida, Kazuhiko Ino, Yoshiyuki Ishida, Hiroaki Kajiyama, Eiko Yamamoto, Kiyosumi Shibata, Mikio Terauchi, Akihiro Nawa, Hidetoshi Akimoto, Osamu Takikawa, Ken Ichi Isobe, Fumitaka Kikkawa

研究成果: Article査読

49 被引用数 (Scopus)

抄録

Purpose: Indoleamine 2,3-dioxygenase (IDO) is a tryptophan-catabolizing enzyme that induces immune tolerance in mice. Our prior study showed that high tumoral IDO expression in endometrial cancer tissues correlates with disease progression and impaired patient survival. The purpose of the present study was to clarify the functional role of IDO in human endometrial cancer cells and to investigate the therapeutic potential of IDO inhibitors. Experimental Design: IDO cDNA was transfected into the human endometrial carcinoma cell line AMEC, resulting in the establishment of stable clones of IDO-overexpressing AMEC cells (AMEC-IDO). AMEC-IDO cells were characterized in vitro as well as in vivo using a mouse xenograft model. Results: There was no significant difference in in vitro cell proliferation, migration, or chemosensitivity to paclitaxel between AMEC-IDO and control vector - transfected cells (AMEC-pcDNA). However, in vivo tumor growth was markedly enhanced in AMEC-IDO - xenografted nude mice when compared with AMEC-pcDNA - xenografted mice. Splenic natural killer (NK) cell counts in AMEC-IDO - xenografted mice were significantly decreased when compared with control mice. Furthermore, conditioned medium obtained from AMEC-IDO cell cultures markedly reduced the NK lysis activity of nude mice. Finally, oral administration of the IDO inhibitor 1-methyl-D-tryptophan in combination with paclitaxel in AMEC-IDO - xenografted mice strongly potentiated the antitumor effect of paclitaxel, resulting in significantly prolonged survival. Conclusions: This is the first evidence showing that IDO overexpression in human cancer cells contributes to tumor progression in vivo with suppression of NK cells. Our data suggest that targeting IDO may be a novel therapeutic strategy for endometrial cancer.

本文言語English
ページ(範囲)7251-7259
ページ数9
ジャーナルClinical Cancer Research
14
22
DOI
出版ステータスPublished - 15-11-2008
外部発表はい

All Science Journal Classification (ASJC) codes

  • 腫瘍学
  • 癌研究

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