期刊
EUROPEAN JOURNAL OF PHARMACOLOGY
卷 887, 期 -, 页码 -出版社
ELSEVIER
DOI: 10.1016/j.ejphar.2020.173584
关键词
p53; EGFR; Gastric cancer; Naphthalimide derivative; NA20
资金
- Natural Science Foundation of China [81960668, 81871636]
- Cultivation Project of Guangxi Normal University for Transformation of Scientific and Technological Achievements [2019PY001]
- Natural Science Foundation of Guangxi Province [2017GXNSFAA198076]
- Foundation of State Key Laboratory of Pharmaceutical Biotechnology, Ministry of Science and Technology of China
- Foundation of State Key Laboratory for the Chemistry and Molecular Engineering of Medicinal Resources, Ministry of Science and Technology of China
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.
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