Open AccessPRIMA‐1 induces p53‐mediated apoptosis by upregulating Noxa in esophageal squamous cell carcinoma with TP53 missense mutation
Author(s) -
Furukawa Haruna,
Makino Tomoki,
Yamasaki Makoto,
Tanaka Koji,
Miyazaki Yasuhiro,
Takahashi Tsuyoshi,
Kurokawa Yukinori,
Nakajima Kiyokazu,
Takiguchi Shuji,
Mori Masaki,
Doki Yuichiro
Publication year - 2018
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.13454
Subject(s) - apoptosis , missense mutation , cancer research , gene knockdown , downregulation and upregulation , cell culture , biology , cell growth , microbiology and biotechnology , chemistry , mutation , genetics , gene
TP 53 is associated with the resistance of cytotoxic treatment and patient prognosis, and the mutation rate of TP 53 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 TP 53; however, its antitumor effect and mechanism in ESCC remain unclear. After evaluating the TP 53 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 p 53‐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 TP 53 missense mutations, whereas no apoptosis was induced in ESCC with wild‐type TP 53 and TP 53 with frameshift and nonsense mutations. Importantly, the knockdown of Noxa canceled the apoptosis induced by PRIMA treatment in ESCC cell lines with TP 53 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 TP 53 missense mutation. PRIMA ‐1 exhibits a significant antitumor effect, inducing massive apoptosis through the upregulation of Noxa in ESCC with TP 53 missense mutations.