論文 - 詳細
| RRC ID | 56136 |
|---|---|
| 著者 | Furukawa H, Makino T, Yamasaki M, Tanaka K, Miyazaki Y, Takahashi T, Kurokawa Y, Nakajima K, Takiguchi S, Mori M, Doki Y. |
| タイトル | PRIMA-1 induces p53-mediated apoptosis by upregulating Noxa in esophageal squamous cell carcinoma with TP53 missense mutation. |
| ジャーナル | Cancer Sci |
| Abstract |
TP53 is associated with the resistance of cytotoxic treatment and patient prognosis, and the mutation rate of TP53 in esophageal squamous cell carcinoma (ESCC) is extraordinarily high, at over 90%. PRIMA-1 (p53 re-activation and induction of massive apoptosis) has recently been reported to restore the function of mutant TP53; however, its antitumor effect and mechanism in ESCC remain unclear. After evaluating the TP53 mutation status of a panel of 11 ESCC cell lines by Sanger sequencing, we assessed the in vitro effect of PRIMA-1 administration on cells with different TP53 status by conducting cell viability and apoptosis assays. The expression levels of proteins in p53-related pathways were examined by Western blotting, while knockdown studies were conducted to investigate the mechanism underlying PRIMA-1's function. An ESCC xenograft model was further used to evaluate the therapeutic effect of PRIMA-1 in vivo. PRIMA-1 markedly inhibited cell growth and induced apoptosis by upregulating Noxa expression in ESCC cell lines with TP53 missense mutations, whereas no apoptosis was induced in ESCC with wild-type TP53 and TP53 with frameshift and nonsense mutations. Importantly, the knockdown of Noxa canceled the apoptosis induced by PRIMA treatment in ESCC cell lines with TP53 missense mutations. PRIMA-1 administration, compared with placebo, showed a significant antitumor effect by inducing Noxa in the xenograft model of an ESCC cell line with a TP53 missense mutation. PRIMA-1 exhibits a significant antitumor effect, inducing massive apoptosis through the upregulation of Noxa in ESCC with TP53 missense mutations. |
| 巻・号 | 109(2) |
| ページ | 412-421 |
| 公開日 | 2018-2-1 |
| DOI | 10.1111/cas.13454 |
| PMID | 29168598 |
| PMC | PMC5797815 |
| MeSH | Animals Apoptosis Aza Compounds / administration & dosage* Aza Compounds / pharmacology Bridged Bicyclo Compounds, Heterocyclic / administration & dosage* Bridged Bicyclo Compounds, Heterocyclic / pharmacology Carcinoma, Squamous Cell / drug therapy* Carcinoma, Squamous Cell / genetics Carcinoma, Squamous Cell / metabolism Cell Line, Tumor Cell Proliferation / drug effects Cell Survival / drug effects Esophageal Neoplasms / drug therapy* Esophageal Neoplasms / genetics Esophageal Neoplasms / metabolism Esophageal Squamous Cell Carcinoma Gene Expression Regulation, Neoplastic / drug effects Humans Mice Mutation, Missense* Proto-Oncogene Proteins c-bcl-2 / metabolism* Sequence Analysis, DNA Tumor Suppressor Protein p53 / genetics* Tumor Suppressor Protein p53 / metabolism Up-Regulation* Xenograft Model Antitumor Assays |
| IF | 4.751 |
| 引用数 | 3 |
| オルトメトリクス指標 |
オルトメトリクス指標項目
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| 各媒体での言及数の合計 | 0 |
| リソース情報 | |
| ヒト・動物細胞 | TE-1(RCB1894) TE-4(RCB2097) TE-5(RCB1949) TE-6(RCB1950) TE-8(RCB2098) TE-9(RCB1988) TE-10(RCB2099) TE-11(RCB2100) TE-14(RCB2101) |