RRC ID 60086
著者 Imanishi M, Yamamoto Y, Wang X, Sugaya A, Hirose M, Endo S, Natori Y, Yamato K, Hyodo I.
タイトル Augmented antitumor activity of 5-fluorouracil by double knockdown of MDM4 and MDM2 in colon and gastric cancer cells.
ジャーナル Cancer Sci
Abstract 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.
巻・号 110(2)
ページ 639-649
公開日 2019-2-1
DOI 10.1111/cas.13893
PMID 30488540
PMC PMC6361612
MeSH Animals Antineoplastic Agents / pharmacology* Cell Cycle Proteins Cell Line, Tumor Cell Proliferation / drug effects Cell Proliferation / genetics Colonic Neoplasms / drug therapy* Colonic Neoplasms / genetics Female Fluorouracil / pharmacology* G1 Phase / drug effects G1 Phase / genetics Gene Expression Regulation, Neoplastic / drug effects HCT116 Cells Humans Mice Mice, Inbred BALB C Mice, Nude Nuclear Proteins / genetics* Proto-Oncogene Proteins / genetics* Proto-Oncogene Proteins c-mdm2 / genetics* Stomach Neoplasms / drug therapy* Stomach Neoplasms / genetics Tumor Suppressor Protein p53 / genetics Up-Regulation / drug effects Up-Regulation / genetics
IF 4.751
引用数 3
リソース情報
ヒト・動物細胞 NUGC-4(RCB1939)