Open AccessAugmented antitumor activity of 5‐fluorouracil by double knockdown of MDM 4 and MDM 2 in colon and gastric cancer cells
Author(s) -
Imanishi Mamiko,
Yamamoto Yoshiyuki,
Wang Xiaoxuan,
Sugaya Akinori,
Hirose Mitsuaki,
Endo Shinji,
Natori Yukikazu,
Yamato Kenji,
Hyodo Ichinosuke
Publication year - 2019
Publication title -
cancer science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.035
H-Index - 141
eISSN - 1349-7006
pISSN - 1347-9032
DOI - 10.1111/cas.13893
Subject(s) - gene knockdown , cancer research , chemistry , microbiology and biotechnology , cell growth , transfection , downregulation and upregulation , cancer , in vivo , apoptosis , biology , gene , biochemistry , genetics
Inactivation of the TP 53 tumor suppressor gene is essential during cancer development and progression. Mutations of TP 53 are often missense and occur in various human cancers. In some fraction of wild‐type (wt) TP 53 tumors, p53 is inactivated by upregulated murine double minute homolog 2 ( MDM 2) and MDM 4. We previously reported that simultaneous knockdown of MDM 4 and MDM 2 using synthetic DNA ‐modified si RNA s revived p53 activity and synergistically inhibited in vitro cell growth in cancer cells with wt TP 53 and high MDM 4 expression (wt TP 53 /high MDM 4). In the present study, MDM 4 / MDM 2 double knockdown with the si RNA s enhanced 5‐fluorouracil (5‐ FU )‐induced p53 activation, arrested the cell cycle at G 1 phase, and potentiated the antitumor effect of 5‐ FU in wt TP 53 /high MDM 4 human colon ( HCT 116 and LoVo) and gastric ( SNU ‐1 and NUGC ‐4) cancer cells. Exposure to 5‐ FU alone induced MDM 2 as well as p21 and PUMA by p53 activation. As p53‐ MDM 2 forms a negative feedback loop, enhancement of the antitumor effect of 5‐ FU by MDM 4 / MDM 2 double knockdown could be attributed to blocking of the feedback mechanism in addition to direct suppression of these p53 antagonists. Intratumor injection of the MDM 4/ MDM 2 si RNA s suppressed in vivo tumor growth and boosted the antitumor effect of 5‐ FU in an athymic mouse xenograft model using HCT 116 cells. These results suggest that a combination of MDM 4 / MDM 2 knockdown and conventional cytotoxic drugs could be a promising treatment strategy for wt TP 53 /high MDM 4 gastrointestinal cancers.