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
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)