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  1. 医学医療系 (Faculty of Medicine)
  2. 兵頭 一之介 (Hyodo Ichinosuke)
  1. 医学医療系 (Faculty of Medicine)
  2. 廣瀬 充明 (Hirose Mitsuaki)
  1. コンテンツタイプ (Contents Type)
  2. 雑誌発表論文等 (Journal article, etc.)
  3. C~
  4. Cancer science

Augmented antitumor activity of 5‐fluorouracil by double knockdown of MDM4 and MDM2 in colon and gastric cancer cells

http://hdl.handle.net/2241/00157078
f5854d43-9abe-4d7b-b5bd-88f188d24a0e
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CS_110-2.pdf CS_110-2 (540.7 kB)
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item type Journal Article(1)
公開日 2019-07-09
タイトル
タイトル Augmented antitumor activity of 5‐fluorouracil by double knockdown of MDM4 and MDM2 in colon and gastric cancer cells
言語
言語 eng
資源タイプ
タイプ journal article
著者 廣瀬, 充明

× 廣瀬, 充明

WEKO 204735
e-Rad 30836987
筑波大学研究者総覧 0000003755

廣瀬, 充明

ja-Kana ヒロセ, ミツアキ

en HIROSE, Mitsuaki

Search repository
兵頭, 一之介

× 兵頭, 一之介

WEKO 713
e-Rad 60416469
筑波大学研究者総覧 0000001705

兵頭, 一之介

ja-Kana ヒョウドウ, イチノスケ

en HYODO, Ichinosuke

Search repository
Imanishi, Mamiko

× Imanishi, Mamiko

WEKO 212373

en Imanishi, Mamiko

Search repository
Yamamoto, Yoshiyuki

× Yamamoto, Yoshiyuki

WEKO 212374

en Yamamoto, Yoshiyuki

Search repository
Wang, Xiaoxuan

× Wang, Xiaoxuan

WEKO 212375

en Wang, Xiaoxuan

Search repository
Sugaya, Akinori

× Sugaya, Akinori

WEKO 212376

en Sugaya, Akinori

Search repository
Endo, Shinji

× Endo, Shinji

WEKO 212377

en Endo, Shinji

Search repository
Natori, Yukikazu

× Natori, Yukikazu

WEKO 212378

en Natori, Yukikazu

Search repository
Yamato, Kenji

× Yamato, Kenji

WEKO 212379

en Yamato, Kenji

Search repository
抄録
内容記述 Inactivation of the TP53 tumor suppressor gene is essential during cancer development and progression. Mutations of TP53 are often missense and occur in various human cancers. In some fraction of wild‐type (wt) TP53 tumors, p53 is inactivated by upregulated murine double minute homolog 2 (MDM2) and MDM4. We previously reported that simultaneous knockdown of MDM4 and MDM2 using synthetic DNA‐modified siRNAs revived p53 activity and synergistically inhibited in vitro cell growth in cancer cells with wt TP53 and high MDM4 expression (wtTP53/highMDM4). In the present study, MDM4/MDM2 double knockdown with the siRNAs enhanced 5‐fluorouracil (5‐FU)‐induced p53 activation, arrested the cell cycle at G1 phase, and potentiated the antitumor effect of 5‐FU in wtTP53/highMDM4 human colon (HCT116 and LoVo) and gastric (SNU‐1 and NUGC‐4) cancer cells. Exposure to 5‐FU alone induced MDM2 as well as p21 and PUMA by p53 activation. As p53‐MDM2 forms a negative feedback loop, enhancement of the antitumor effect of 5‐FU by MDM4/MDM2 double knockdown could be attributed to blocking of the feedback mechanism in addition to direct suppression of these p53 antagonists. Intratumor injection of the MDM4/MDM2 siRNAs suppressed in vivo tumor growth and boosted the antitumor effect of 5‐FU in an athymic mouse xenograft model using HCT116 cells. These results suggest that a combination of MDM4/MDM2 knockdown and conventional cytotoxic drugs could be a promising treatment strategy for wtTP53/highMDM4 gastrointestinal cancers.
書誌情報 Cancer Science

巻 110, 号 2, p. 639-649, 発行日 2018-11
ISSN
収録物識別子 1347-9032
書誌レコードID
収録物識別子 AA11808050
PubMed番号
関連識別子
関連識別子 30488540
DOI
関連識別子
関連識別子 10.1111/cas.13893
権利
権利情報 © 2018 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.
権利
権利情報 This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.
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出版者 Wiley
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