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1.
Mol Cancer Ther ; 18(5): 886-899, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30926635

RESUMO

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.

2.
Mol Cell Oncol ; 5(3): e1327005, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30250883

RESUMO

Selective clearance of damaged mitochondria can reverse pathological status in chronic inflammatory diseases. We recently identified a critical role of nuclear receptor Nur77 and celastrol in priming inflamed mitochondria for autophagy through its mitochondrial targeting and interaction with tumor necrosis factor receptor-associated factor 2 (TRAF2) and the autophagic adaptor p62/SQSTM1.

3.
Nat Commun ; 8: 16066, 2017 07 17.
Artigo em Inglês | MEDLINE | ID: mdl-28714476

RESUMO

Retinoid X receptor-alpha (RXRα) binds to DNA either as homodimers or heterodimers, but it also forms homotetramers whose function is poorly defined. We previously discovered that an N-terminally-cleaved form of RXRα (tRXRα), produced in tumour cells, activates phosphoinositide 3-kinase (PI3K) signalling by binding to the p85α subunit of PI3K and that K-80003, an anti-cancer agent, inhibits this process. Here, we report through crystallographic and biochemical studies that K-80003 binds to and stabilizes tRXRα tetramers via a 'three-pronged' combination of canonical and non-canonical mechanisms. K-80003 binding has no effect on tetramerization of RXRα, owing to the head-tail interaction that is absent in tRXRα. We also identify an LxxLL motif in p85α, which binds to the coactivator-binding groove on tRXRα and dissociates from tRXRα upon tRXRα tetramerization. These results identify conformational selection as the mechanism for inhibiting the nongenomic action of tRXRα and provide molecular insights into the development of RXRα cancer therapeutics.

4.
Mol Cell ; 66(1): 141-153.e6, 2017 Apr 06.
Artigo em Inglês | MEDLINE | ID: mdl-28388439

RESUMO

Mitochondria play an integral role in cell death, autophagy, immunity, and inflammation. We previously showed that Nur77, an orphan nuclear receptor, induces apoptosis by targeting mitochondria. Here, we report that celastrol, a potent anti-inflammatory pentacyclic triterpene, binds Nur77 to inhibit inflammation and induce autophagy in a Nur77-dependent manner. Celastrol promotes Nur77 translocation from the nucleus to mitochondria, where it interacts with tumor necrosis factor receptor-associated factor 2 (TRAF2), a scaffold protein and E3 ubiquitin ligase important for inflammatory signaling. The interaction is mediated by an LxxLL motif in TRAF2 and results not only in the inhibition of TRAF2 ubiquitination but also in Lys63-linked Nur77 ubiquitination. Under inflammatory conditions, ubiquitinated Nur77 resides at mitochondria, rendering them sensitive to autophagy, an event involving Nur77 interaction with p62/SQSTM1. Together, our results identify Nur77 as a critical intracellular target for celastrol and unravel a mechanism of Nur77-dependent clearance of inflamed mitochondria to alleviate inflammation.


Assuntos
Anti-Inflamatórios/farmacologia , Autofagia/efeitos dos fármacos , Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Mitocôndrias Hepáticas/efeitos dos fármacos , Degradação Mitocondrial/efeitos dos fármacos , Membro 1 do Grupo A da Subfamília 4 de Receptores Nucleares/metabolismo , Fator 2 Associado a Receptor de TNF/metabolismo , Triterpenos/farmacologia , Ubiquitinação/efeitos dos fármacos , Transporte Ativo do Núcleo Celular , Animais , Anti-Inflamatórios/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/genética , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Modelos Animais de Doenças , Feminino , Genótipo , Células HEK293 , Células HeLa , Células Hep G2 , Humanos , Ligantes , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mitocôndrias Hepáticas/metabolismo , Mitocôndrias Hepáticas/patologia , Membro 1 do Grupo A da Subfamília 4 de Receptores Nucleares/deficiência , Membro 1 do Grupo A da Subfamília 4 de Receptores Nucleares/genética , Fenótipo , Ligação Proteica , Domínios e Motivos de Interação entre Proteínas , Interferência de RNA , Proteína Sequestossoma-1/genética , Proteína Sequestossoma-1/metabolismo , Transdução de Sinais/efeitos dos fármacos , Fator 2 Associado a Receptor de TNF/genética , Transfecção , Triterpenos/metabolismo
5.
Br J Pharmacol ; 173(2): 344-56, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26505879

RESUMO

BACKGROUND AND PURPOSE: The orphan nuclear receptor Nur77 is implicated in the survival and apoptosis of cancer cells. The purpose of this study was to determine whether and how Nur77 serves to mediate the effect of the inflammatory cytokine TNF-α in cancer cells and to identify and characterize new agents targeting Nur77 for cancer therapy. EXPERIMENTAL APPROACH: The effects of TNF-α on the expression and function of Nur77 were studied using in vitro and in vivo models. Nur77 expression was evaluated in tumour tissues from breast cancer patients. The anticancer effects of honokiol and its mechanism of action were assessed by in vitro, cell-based and animal studies. KEY RESULTS: TNF-α rapidly and potently induced the expression of Nur77 in breast cancer cells through activation of IκB kinase and JNK. Knocking down Nur77 resulted in TNF-α-dependent apoptosis, while ectopic Nur77 expression in MCF-7 cells promoted their growth in animals. Levels of Nur77 were higher in tumour tissues than the corresponding tissues surrounding the tumour in about 50% breast cancer patients studied. Our in vitro and animal studies also identified honokiol as an effective sensitizer of TNF-α-induced apoptosis by inhibiting TNF-α-induced Nur77 mRNA expression, which could be attributed to its interference of TNFR1's interaction with receptor-interacting protein 1 (RIPK1). CONCLUSIONS AND IMPLICATIONS: TNF-α-induced Nur77 serves as a survival factor to attenuate the death effect of TNF-α in cancer cells. With its proven human safety profile, honokiol represents a promising agent that warrants further clinical development.


Assuntos
Apoptose/efeitos dos fármacos , Compostos de Bifenilo/farmacologia , Neoplasias da Mama/metabolismo , Lignanas/farmacologia , Membro 1 do Grupo A da Subfamília 4 de Receptores Nucleares/antagonistas & inibidores , Membro 1 do Grupo A da Subfamília 4 de Receptores Nucleares/biossíntese , Fator de Necrose Tumoral alfa/farmacologia , Animais , Apoptose/fisiologia , Compostos de Bifenilo/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Medicamentos de Ervas Chinesas/farmacologia , Medicamentos de Ervas Chinesas/uso terapêutico , Feminino , Regulação Neoplásica da Expressão Gênica , Células HeLa , Células Hep G2 , Humanos , Lignanas/uso terapêutico , Células MCF-7 , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Ensaios Antitumorais Modelo de Xenoenxerto/métodos
6.
Cancer Res ; 75(10): 2049-60, 2015 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-25795708

RESUMO

Retinoid X receptor alpha (RXRα) and its N-terminally truncated version, tRXRα, are widely implicated in cancer development and represent intriguing targets for cancer prevention and treatment. Successful manipulation of RXRα and tRXRα requires the identification of their modulators that could produce therapeutic effects. Here, we report that a class of nitrostyrene derivatives bind to RXRα by a unique mechanism, of which the nitro group of nitrostyrene derivatives and Cys432 of RXRα are required for binding. The binding results in the potent activation of Gal4-DBD-RXRα-LBD transactivation. However, the binding inhibits the transactivation of RXRα homodimer, which might be due to the distinct conformation of RXRα homodimer induced by these nitrostyrene derivatives. Two RXRα point mutants with Cys432 substituted with Tyr and Trp, respectively, could mimic the bindings of two nitrostyrene derivatives and have the ability of autotransactivation. In studying the functional consequences of the binding, we show that these nitrostyrene derivatives could potently inhibit the TNFα/NFκB signaling pathway in a tRXRα-dependent manner. tRXRα promotes TNFα-induced NF-κB activation through its interaction with TRAF2 and enhances TNFα-induced ubiquitination of RIP1, which is strongly inhibited by nitrostyrene derivatives. The inhibition of TNFα-induced NF-κB activation results in the synergistic effect of the combination of nitrostyrene derivatives and TNFα on the induction of cancer cell apoptosis. Together, our results show a new class of RXRα modulators that induce apoptosis of cancer cells through their unique binding mode and new mechanism of action.


Assuntos
Antracenos/farmacologia , Antineoplásicos/farmacologia , NF-kappa B/metabolismo , Naftalenos/farmacologia , Receptor X Retinoide alfa/metabolismo , Estirenos/farmacologia , Fator de Necrose Tumoral alfa/fisiologia , Animais , Apoptose , Células HEK293 , Humanos , Células MCF-7 , Camundongos Endogâmicos BALB C , Camundongos Nus , NF-kappa B/genética , Ligação Proteica , Receptor X Retinoide alfa/agonistas , Transdução de Sinais , Fator 2 Associado a Receptor de TNF/metabolismo , Ativação Transcricional , Ubiquitinação , Ensaios Antitumorais Modelo de Xenoenxerto
7.
Chem Biol ; 21(5): 596-607, 2014 May 22.
Artigo em Inglês | MEDLINE | ID: mdl-24704507

RESUMO

Retinoid X receptor-alpha (RXRα), an intriguing and unique drug target, can serve as an intracellular target mediating the anticancer effects of certain nonsteroidal anti-inflammatory drugs (NSAIDs), including sulindac. We report the synthesis and characterization of two sulindac analogs, K-8008 and K-8012, which exert improved anticancer activities over sulindac in a RXRα-dependent manner. The analogs inhibit the interaction of the N-terminally truncated RXRα (tRXRα) with the p85α subunit of PI3K, leading to suppression of AKT activation and induction of apoptosis. Crystal structures of the RXRα ligand-binding domain (LBD) with K-8008 or K-8012 reveal that both compounds bind to tetrameric RXRα LBD at a site different from the classical ligand-binding pocket. Thus, these results identify K-8008 and K-8012 as tRXRα modulators and define a binding mechanism for regulating the nongenomic action of tRXRα.


Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Neoplasias/tratamento farmacológico , Receptor X Retinoide alfa/antagonistas & inibidores , Receptor X Retinoide alfa/química , Sulindaco/análogos & derivados , Sulindaco/farmacologia , Animais , Antineoplásicos/síntese química , Sítios de Ligação/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Células HeLa , Células Hep G2 , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Modelos Moleculares , Estrutura Molecular , Neoplasias/metabolismo , Neoplasias/patologia , Receptor X Retinoide alfa/metabolismo , Relação Estrutura-Atividade , Sulindaco/química , Células Tumorais Cultivadas
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