PRIMA-1 induces p53-mediated apoptosis by upregulating Noxa in esophageal squamous cell carcinoma with TP53 missense mutation

Haruna Furukawa, Tomoki Makino, Makoto Yamasaki, Koji Tanaka, Yasuhiro Miyazaki, Tsuyoshi Takahashi, Yukinori Kurokawa, Kiyokazu Nakajima, Shuji Takiguchi, Masaki Mori, Yuichiro Doki

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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.

Original languageEnglish
Pages (from-to)412-421
Number of pages10
JournalCancer Science
Volume109
Issue number2
DOIs
Publication statusPublished - Feb 1 2018
Externally publishedYes

Fingerprint

Noxae
Missense Mutation
Apoptosis
Cell Line
Heterografts
2,2-bis(hydroxymethyl)-1-azabicyclo(2,2,2,)octan-3-one
Esophageal Squamous Cell Carcinoma
Frameshift Mutation
Nonsense Codon
Therapeutic Uses
Mutation Rate
Cell Survival
Up-Regulation
Western Blotting
Placebos

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

Furukawa, H., Makino, T., Yamasaki, M., Tanaka, K., Miyazaki, Y., Takahashi, T., ... Doki, Y. (2018). PRIMA-1 induces p53-mediated apoptosis by upregulating Noxa in esophageal squamous cell carcinoma with TP53 missense mutation. Cancer Science, 109(2), 412-421. https://doi.org/10.1111/cas.13454

PRIMA-1 induces p53-mediated apoptosis by upregulating Noxa in esophageal squamous cell carcinoma with TP53 missense mutation. / Furukawa, Haruna; Makino, Tomoki; Yamasaki, Makoto; Tanaka, Koji; Miyazaki, Yasuhiro; Takahashi, Tsuyoshi; Kurokawa, Yukinori; Nakajima, Kiyokazu; Takiguchi, Shuji; Mori, Masaki; Doki, Yuichiro.

In: Cancer Science, Vol. 109, No. 2, 01.02.2018, p. 412-421.

Research output: Contribution to journalArticle

Furukawa, H, Makino, T, Yamasaki, M, Tanaka, K, Miyazaki, Y, Takahashi, T, Kurokawa, Y, Nakajima, K, Takiguchi, S, Mori, M & Doki, Y 2018, 'PRIMA-1 induces p53-mediated apoptosis by upregulating Noxa in esophageal squamous cell carcinoma with TP53 missense mutation', Cancer Science, vol. 109, no. 2, pp. 412-421. https://doi.org/10.1111/cas.13454
Furukawa, Haruna ; Makino, Tomoki ; Yamasaki, Makoto ; Tanaka, Koji ; Miyazaki, Yasuhiro ; Takahashi, Tsuyoshi ; Kurokawa, Yukinori ; Nakajima, Kiyokazu ; Takiguchi, Shuji ; Mori, Masaki ; Doki, Yuichiro. / PRIMA-1 induces p53-mediated apoptosis by upregulating Noxa in esophageal squamous cell carcinoma with TP53 missense mutation. In: Cancer Science. 2018 ; Vol. 109, No. 2. pp. 412-421.
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