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BI1071, a Novel Nur77 Modulator, Induces Apoptosis of Cancer Cells by Activating the Nur77-Bcl-2 Apoptotic Pathway.
Mol Cancer Ther ; 18(5): 886-899, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30926635
ABSTRACT
Nur77 (also called TR3 or NGFI-B), an orphan member of the nuclear receptor superfamily, induces apoptosis by translocating to mitochondria where it interacts with Bcl-2 to convert Bcl-2 from an antiapoptotic to a pro-apoptotic molecule. Nur77 posttranslational modification such as phosphorylation has been shown to induce Nur77 translocation from the nucleus to mitochondria. However, small molecules that can bind directly to Nur77 to trigger its mitochondrial localization and Bcl-2 interaction remain to be explored. Here, we report our identification and characterization of DIM-C-pPhCF3 +MeSO3 - (BI1071), an oxidized product derived from indole-3-carbinol metabolite, as a modulator of the Nur77-Bcl-2 apoptotic pathway. BI1071 binds Nur77 with high affinity, promotes Nur77 mitochondrial targeting and interaction with Bcl-2, and effectively induces apoptosis of cancer cells in a Nur77- and Bcl-2-dependent manner. Studies with animal model showed that BI1071 potently inhibited the growth of tumor cells in animals through its induction of apoptosis. Our results identify BI1071 as a novel Nur77-binding modulator of the Nur77-Bcl-2 apoptotic pathway, which may serve as a promising lead for treating cancers with overexpression of Bcl-2.

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Texto completo: Disponível Coleções: Bases de dados internacionais Base de dados: MEDLINE Idioma: Inglês Revista: Mol Cancer Ther Assunto da revista: Antineoplasicos Ano de publicação: 2019 Tipo de documento: Artigo País de afiliação: China