RRC ID |
56136
|
Author |
Furukawa H, Makino T, Yamasaki M, Tanaka K, Miyazaki Y, Takahashi T, Kurokawa Y, Nakajima K, Takiguchi S, Mori M, Doki Y.
|
Title |
PRIMA-1 induces p53-mediated apoptosis by upregulating Noxa in esophageal squamous cell carcinoma with TP53 missense mutation.
|
Journal |
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.
|
Volume |
109(2)
|
Pages |
412-421
|
Published |
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
|
Times Cited |
3
|
Resource |
Human and Animal Cells |
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) |