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Targeting DNA and mutant p53 by a naphthalimide derivative, NA20, exhibits selective inhibition in gastric tumorigenesis by blocking mutant p53-EGFR signaling pathway.

Abstract：

:Mutations of p53 in cancer cells not only subvert its antiproliferative properties but can also promote various oncogenic responses through a gain-of-function activity. Pharmacological manipulation of the mutant p53 pathway by specific compounds could be an effective strategy for cancer therapy. We show here that gain-of-function p53 mutation in gastric cancer cells promotes tumorigenesis by enhancing p53-EGFR (epidermal growth factor receptor) signaling pathway, and such process can be blocked by small molecule NA20, a naphthalimide derivative that exhibited selective inhibition in p53 mutant gastric cancer cell lines. We found that targeting DNA and blocking the mutant p53-drived carcinogenicity accounted for the primary antitumor effect of NA20 in gastric tumor models. NA20 bound to DNA and p53 identified by a combination of drug tracking, DNA relaxation assay and coimmunoprecipitation-mass spectrometry (CoIP-MS) detection, which led to the p21 activation and the suppression of EGFR signal cascading, thereby evoking cell cycle arrest and cell apoptosis, finally leading to cancer cell inhibition both in vitro and in vivo. Taken together, these results suggest that NA20 may be a potential candidate for gastric cancer therapy.

journal_name

Eur J Pharmacol

journal_title

European journal of pharmacology

authors

Zhang G,Li L,Bi J,Wu Y,Li E

doi

10.1016/j.ejphar.2020.173584

subject

Has Abstract

pub_date

2020-11-15 00:00:00

pages

173584

eissn

0014-2999

issn

1879-0712

pii

S0014-2999(20)30676-2

journal_volume

887

pub_type

杂志文章

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