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Nutlin‐3, a MDM2 antagonist, induces Erk1/2 activation in U2OS cells
Author(s) -
Lee SunYoung,
Ko KyoungWon,
Choe YunJung,
Jeong SeongWhan,
Kim HoShik
Publication year - 2010
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.24.1_supplement.485.16
Subject(s) - apoptosis , mdm2 , cancer research , cycloheximide , mapk/erk pathway , programmed cell death , cell growth , microbiology and biotechnology , chemistry , cell cycle checkpoint , cell cycle , kinase , cancer cell , downregulation and upregulation , cell culture , biology , cancer , biochemistry , genetics , gene
Nutlin‐3 is a small molecular antagonist of MDM2 which is a critical negative regulator of p53. Activation of p53 by nutlin‐3 has been reported to trigger cell cycle arrest and apoptosis in cancer cells. Here, we present that nutlin‐3 activates anti‐apoptotic pathway as well as apoptosis in human osteosarcoma U2OS cells. Nutlin‐3 inhibited growth of U2OS cells, which was associated with apoptosis. Concomitantly, Erk1/2 was phosphorylated by nutlin‐3 treatment. Pretreatment of MEK inhibitors such as U0126 and PD98059 enhanced cell death by nutlin‐3, suggesting that activated Erk1/2 protects U2OS cells from apoptosis. In addition, nutlin‐3 induced transcription of EGFR ligands including HB‐EGF and Erk1/2 phosphorylation by nutlin‐3 was prevented by cycloheximide, implying that Erk1/2 activation might be resulted from autostimulation of EGFR by upregulated EGFR ligands. Taken together, p53 activation by nutlin‐3 may induce both apoptotic and survival pathways consisted of Erk1/2. Therefore, combined treatment of nutlin‐3 and Erk1/2 inhibitors may enhance therapeutic efficacy of p53 activation to induce cancer cell apoptosis. This research was supported by MRC from cell death disease research center funded by KOSEF.