Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 33
Filtrar
1.
Mol Cell ; 78(6): 1192-1206.e10, 2020 06 18.
Artigo em Inglês | MEDLINE | ID: mdl-32470318

RESUMO

Tumor-derived extracellular vesicles are important mediators of cell-to-cell communication during tumorigenesis. Here, we demonstrated that hepatocellular carcinoma (HCC)-derived ectosomes remodel the tumor microenvironment to facilitate HCC progression in an ectosomal PKM2-dependent manner. HCC-derived ectosomal PKM2 induced not only metabolic reprogramming in monocytes but also STAT3 phosphorylation in the nucleus to upregulate differentiation-associated transcription factors, leading to monocyte-to-macrophage differentiation and tumor microenvironment remodeling. In HCC cells, sumoylation of PKM2 induced its plasma membrane targeting and subsequent ectosomal excretion via interactions with ARRDC1. The PKM2-ARRDC1 association in HCC was reinforced by macrophage-secreted cytokines/chemokines in a CCL1-CCR8 axis-dependent manner, further facilitating PKM2 excretion from HCC cells to form a feedforward regulatory loop for tumorigenesis. In the clinic, ectosomal PKM2 was clearly detected in the plasma of HCC patients. This study highlights a mechanism by which ectosomal PKM2 remodels the tumor microenvironment and reveals ectosomal PKM2 as a potential diagnostic marker for HCC.


Assuntos
Proteínas de Transporte/metabolismo , Micropartículas Derivadas de Células/metabolismo , Proteínas de Membrana/metabolismo , Hormônios Tireóideos/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Proteínas de Transporte/genética , Diferenciação Celular/genética , Linhagem Celular Tumoral , Proliferação de Células/genética , Micropartículas Derivadas de Células/genética , Micropartículas Derivadas de Células/patologia , Quimiocina CCL1/metabolismo , Progressão da Doença , Células Hep G2 , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Macrófagos/metabolismo , Masculino , Proteínas de Membrana/genética , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Monócitos/metabolismo , Prognóstico , Fator de Transcrição STAT3/metabolismo , Hormônios Tireóideos/genética , Microambiente Tumoral , Proteínas de Ligação a Hormônio da Tireoide
2.
Mol Cell ; 69(3): 480-492.e7, 2018 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-29395065

RESUMO

Fatty acid oxidation (FAO) is crucial for cells to overcome metabolic stress by providing ATP and NADPH. However, the mechanism by which FAO is regulated in tumors remains elusive. Here we show that Nur77 is required for the metabolic adaptation of melanoma cells by protecting FAO. Glucose deprivation activates ERK2 to phosphorylate and induce Nur77 translocation to the mitochondria, where Nur77 binds to TPß, a rate-limiting enzyme in FAO. Although TPß activity is normally inhibited by oxidation under glucose deprivation, the Nur77-TPß association results in Nur77 self-sacrifice to protect TPß from oxidation. FAO is therefore able to maintain NADPH and ATP levels and prevent ROS increase and cell death. The Nur77-TPß interaction further promotes melanoma metastasis by facilitating circulating melanoma cell survival. This study demonstrates a novel regulatory function of Nur77 with linkage of the FAO-NADPH-ROS pathway during metabolic stress, suggesting Nur77 as a potential therapeutic target in melanoma.


Assuntos
Melanoma/metabolismo , Membro 1 do Grupo A da Subfamília 4 de Receptores Nucleares/metabolismo , Animais , Sobrevivência Celular/fisiologia , Ácidos Graxos/metabolismo , Glucose/metabolismo , Células HEK293 , Humanos , Metabolismo dos Lipídeos , Melanoma/patologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Mitocôndrias/metabolismo , Subunidade beta da Proteína Mitocondrial Trifuncional/metabolismo , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Estresse Oxidativo/fisiologia , Espécies Reativas de Oxigênio/metabolismo
3.
Proc Natl Acad Sci U S A ; 117(44): 27412-27422, 2020 11 03.
Artigo em Inglês | MEDLINE | ID: mdl-33087562

RESUMO

Nuclear receptor Nur77 participates in multiple metabolic regulations and plays paradoxical roles in tumorigeneses. Herein, we demonstrated that the knockout of Nur77 stimulated mammary tumor development in two mouse models, which would be reversed by a specific reexpression of Nur77 in mammary tissues. Mechanistically, Nur77 interacted and recruited corepressors, the SWI/SNF complex, to the promoters of CD36 and FABP4 to suppress their transcriptions, which hampered the fatty acid uptake, leading to the inhibition of cell proliferation. Peroxisome proliferator-activated receptor-γ (PPARγ) played an antagonistic role in this process through binding to Nur77 to facilitate ubiquitin ligase Trim13-mediated ubiquitination and degradation of Nur77. Cocrystallographic and functional analysis revealed that Csn-B, a Nur77-targeting compound, promoted the formation of Nur77 homodimer to prevent PPARγ binding by steric hindrance, thereby strengthening the Nur77's inhibitory role in breast cancer. Therefore, our study reveals a regulatory function of Nur77 in breast cancer via impeding fatty acid uptake.


Assuntos
Neoplasias da Mama/patologia , Membro 1 do Grupo A da Subfamília 4 de Receptores Nucleares/metabolismo , PPAR gama/metabolismo , Fenilacetatos/farmacologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Mama/patologia , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/mortalidade , Proliferação de Células , Proteínas de Ligação a DNA/metabolismo , Modelos Animais de Doenças , Progressão da Doença , Ácidos Graxos/metabolismo , Feminino , Humanos , Estimativa de Kaplan-Meier , Metabolismo dos Lipídeos/efeitos dos fármacos , Glândulas Mamárias Animais/patologia , Camundongos , Pessoa de Meia-Idade , Membro 1 do Grupo A da Subfamília 4 de Receptores Nucleares/agonistas , PPAR gama/agonistas , Cultura Primária de Células , Prognóstico , Proteólise/efeitos dos fármacos , Análise Serial de Tecidos , Células Tumorais Cultivadas , Proteínas Supressoras de Tumor/metabolismo , Ubiquitinação/efeitos dos fármacos
4.
Nat Chem Biol ; 11(5): 339-46, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-25822914

RESUMO

Sepsis, a hyperinflammatory response that can result in multiple organ dysfunctions, is a leading cause of mortality from infection. Here, we show that orphan nuclear receptor Nur77 (also known as TR3) can enhance resistance to lipopolysaccharide (LPS)-induced sepsis in mice by inhibiting NF-κB activity and suppressing aberrant cytokine production. Nur77 directly associates with p65 to block its binding to the κB element. However, this function of Nur77 is countered by the LPS-activated p38α phosphorylation of Nur77. Dampening the interaction between Nur77 and p38α would favor Nur77 suppression of the hyperinflammatory response. A compound, n-pentyl 2-[3,5-dihydroxy-2-(1-nonanoyl) phenyl]acetate, screened from a Nur77-biased library, blocked the Nur77-p38α interaction by targeting the ligand-binding domain of Nur77 and restored the suppression of the hyperinflammatory response through Nur77 inhibition of NF-κB. This study associates the nuclear receptor with immune homeostasis and implicates a new therapeutic strategy to treat hyperinflammatory responses by targeting a p38α substrate to modulate p38α-regulated functions.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Inflamação/prevenção & controle , Lipopolissacarídeos/toxicidade , Membro 1 do Grupo A da Subfamília 4 de Receptores Nucleares/efeitos dos fármacos , Fenilacetatos/farmacologia , Proteínas Quinases p38 Ativadas por Mitógeno/efeitos dos fármacos , Animais , Diabetes Mellitus Tipo 2/complicações , Avaliação Pré-Clínica de Medicamentos , Homeostase/efeitos dos fármacos , Inflamação/induzido quimicamente , Ligantes , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Modelos Moleculares , Conformação Molecular , Sepse/tratamento farmacológico , Sepse/genética , Fator de Transcrição RelA/antagonistas & inibidores
5.
Nat Chem Biol ; 10(2): 133-40, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24316735

RESUMO

Autophagy is linked to cell death, yet the associated mechanisms are largely undercharacterized. We discovered that melanoma, which is generally resistant to drug-induced apoptosis, can undergo autophagic cell death with the participation of orphan nuclear receptor TR3. A sequence of molecular events leading to cellular demise is launched by a specific chemical compound, 1-(3,4,5-trihydroxyphenyl)nonan-1-one, newly acquired from screening a library of TR3-targeting compounds. The autophagic cascade comprises TR3 translocation to mitochondria through interaction with the mitochondrial outer membrane protein Nix, crossing into the mitochondrial inner membrane through Tom40 and Tom70 channel proteins, dissipation of mitochondrial membrane potential by the permeability transition pore complex ANT1-VDAC1 and induction of autophagy. This process leads to excessive mitochondria clearance and irreversible cell death. It implicates a new approach to melanoma therapy through activation of a mitochondrial signaling pathway that integrates a nuclear receptor with autophagy for cell death.


Assuntos
Autofagia , Cetonas/química , Mitocôndrias/fisiologia , Membro 1 do Grupo A da Subfamília 4 de Receptores Nucleares/metabolismo , Pirogalol/análogos & derivados , Transdução de Sinais , Animais , Linhagem Celular Tumoral , Cristalografia por Raios X , Modelos Animais de Doenças , Humanos , Cetonas/farmacologia , Melanoma/tratamento farmacológico , Proteínas de Membrana/metabolismo , Camundongos , Conformação Proteica , Proteínas Proto-Oncogênicas/metabolismo , Pirogalol/química , Pirogalol/farmacologia , Proteínas Supressoras de Tumor/metabolismo
6.
Nat Chem Biol ; 8(11): 897-904, 2012 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-22983157

RESUMO

Liver kinase B1 (LKB1) has important roles in governing energy homeostasis by regulating the activity of the energy sensor kinase AMP-activated protein kinase (AMPK). The regulation of LKB1 function, however, is still poorly understood. Here we demonstrate that the orphan nuclear receptor Nur77 binds and sequesters LKB1 in the nucleus, thereby attenuating AMPK activation. This Nur77 function is antagonized by the chemical compound ethyl 2-[2,3,4-trimethoxy-6-(1-octanoyl)phenyl]acetate (TMPA), which interacts with Nur77 with high affinity and at specific sites. TMPA binding of Nur77 results in the release and shuttling of LKB1 to the cytoplasm to phosphorylate AMPKα. Moreover, TMPA effectively reduces blood glucose and alleviates insulin resistance in type II db/db and high-fat diet- and streptozotocin-induced diabetic mice but not in diabetic littermates with the Nur77 gene knocked out. This study attains a mechanistic understanding of the regulation of LKB1-AMPK axis and implicates Nur77 as a new and amenable target for the design and development of therapeutics to treat metabolic diseases.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Membro 1 do Grupo A da Subfamília 4 de Receptores Nucleares/metabolismo , Fenilacetatos/farmacologia , Proteínas Serina-Treonina Quinases/metabolismo , Quinases Proteína-Quinases Ativadas por AMP , Proteínas Quinases Ativadas por AMP/antagonistas & inibidores , Animais , Glicemia/efeitos dos fármacos , Células Cultivadas , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/metabolismo , Ativação Enzimática/efeitos dos fármacos , Células HEK293 , Humanos , Resistência à Insulina , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Obesos , Modelos Moleculares , Membro 1 do Grupo A da Subfamília 4 de Receptores Nucleares/antagonistas & inibidores , Membro 1 do Grupo A da Subfamília 4 de Receptores Nucleares/genética , Fenilacetatos/química , Fosforilação/efeitos dos fármacos , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Transporte Proteico/efeitos dos fármacos , Estreptozocina , Relação Estrutura-Atividade
7.
Nat Cell Biol ; 26(9): 1545-1557, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-38997456

RESUMO

Gasdermin (GSDM) family proteins, known as the executors of pyroptosis, undergo protease-mediated cleavage before inducing pyroptosis. We here discovered a form of pyroptosis mediated by full-length (FL) GSDME without proteolytic cleavage. Intense ultraviolet-C irradiation-triggered DNA damage activates nuclear PARP1, leading to extensive formation of poly(ADP-ribose) (PAR) polymers. These PAR polymers are released to the cytoplasm, where they activate PARP5 to facilitate GSDME PARylation, resulting in a conformational change in GSDME that relieves autoinhibition. Moreover, ultraviolet-C irradiation promotes cytochrome c-catalysed cardiolipin peroxidation to elevate lipid reactive oxygen species, which is then sensed by PARylated GSDME, leading to oxidative oligomerization and plasma membrane targeting of FL-GSDME for perforation, eventually inducing pyroptosis. Reagents that concurrently stimulate PARylation and oxidation of FL-GSDME, synergistically promoting pyroptotic cell death. Overall, the present findings elucidate an unreported mechanism underlying the cleavage-independent function of GSDME in executing cell death, further enriching the paradigms and understanding of FL-GSDME-mediated pyroptosis.


Assuntos
Piroptose , Humanos , Animais , Camundongos , Poli(ADP-Ribose) Polimerase-1/metabolismo , Poli(ADP-Ribose) Polimerase-1/genética , Dano ao DNA , Espécies Reativas de Oxigênio/metabolismo , Raios Ultravioleta , Células HEK293 , Poli Adenosina Difosfato Ribose/metabolismo , Peroxidação de Lipídeos , Proteólise , Camundongos Endogâmicos C57BL , Cardiolipinas/metabolismo , Gasderminas
8.
Gut ; 61(5): 714-24, 2012 May.
Artigo em Inglês | MEDLINE | ID: mdl-21873734

RESUMO

AIMS: Wnt signalling is involved in cellular homeostasis and development. Dysregulation of the Wnt signalling pathway has been linked to colorectal cancer. The orphan nuclear receptor TR3 plays important roles in proliferation and apoptosis. In this study, we investigated how TR3 suppresses intestinal tumorigenesis by regulating Wnt signalling. METHODS: Intestinal polyps were quantified in Apc(min/+), Apc(min/+)/TR3(-/-) and Apc(min/+)/villin-TR3 mice. Wnt signalling activity was evaluated by assessing ß-galactosidase activity in a BAT-Gal reporter strain. The TR3 agonist cytosporone B was used to evaluate the role of TR3 in intestinal tumorigenesis. Crosstalk between TR3 and ß-catenin/TCF4 was analysed by molecular methods in colorectal cancer cells. The phosphorylation of TR3 by glycogen synthase kinase (GSK) 3ß and the correlation between GSK3ß activity and TR3 phosphorylation were evaluated in clinical samples and colorectal cancer cells. RESULTS: TR3 was found to significantly suppress Wnt signalling activity and the proliferation of intestinal epithelial cells. Apc(min/+)/TR3(-/-) mice developed more intestinal polyps than Apc(min/+)/TR3(+/+) mice, whereas either transgenic overexpression of TR3 in the intestine or treatment with cytosporone B in Apc(min/+) mice significantly decreased intestinal tumour number. Mechanistically, TR3 disrupted the association of ß-catenin and TCF4 on chromatin and facilitated the recruitment of transcriptional co-repressors to the promoters of Wnt signalling target genes. However, TR3 was phosphorylated by GSK3ß in most clinical colorectal cancers, which attenuated the inhibitory activity of TR3 towards Wnt signalling. CONCLUSIONS: TR3 is a negative regulator of Wnt signalling and thus significantly suppresses intestinal tumorigenesis in Apc(min/+) mice. This inhibitory effect of TR3 may be paradoxically overcome through phosphorylation by GSK3ß in clinical colorectal cancers.


Assuntos
Biomarcadores Tumorais/metabolismo , Transformação Celular Neoplásica/metabolismo , Neoplasias Colorretais/metabolismo , Mucosa Intestinal/metabolismo , Membro 1 do Grupo A da Subfamília 4 de Receptores Nucleares/metabolismo , Via de Sinalização Wnt , Animais , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/metabolismo , Proliferação de Células , Neoplasias Colorretais/patologia , Regulação para Baixo , Quinase 3 da Glicogênio Sintase/metabolismo , Glicogênio Sintase Quinase 3 beta , Mucosa Intestinal/patologia , Pólipos Intestinais/metabolismo , Pólipos Intestinais/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fosforilação , Fator de Transcrição 4 , beta Catenina/metabolismo , beta-Galactosidase/metabolismo
9.
Cell Res ; 33(12): 904-922, 2023 12.
Artigo em Inglês | MEDLINE | ID: mdl-37460805

RESUMO

Pyroptosis is a type of regulated cell death executed by gasdermin family members. However, how gasdermin-mediated pyroptosis is negatively regulated remains unclear. Here, we demonstrate that mannose, a hexose, inhibits GSDME-mediated pyroptosis by activating AMP-activated protein kinase (AMPK). Mechanistically, mannose metabolism in the hexosamine biosynthetic pathway increases levels of the metabolite N-acetylglucosamine-6-phosphate (GlcNAc-6P), which binds AMPK to facilitate AMPK phosphorylation by LKB1. Activated AMPK then phosphorylates GSDME at Thr6, which leads to blockade of caspase-3-induced GSDME cleavage, thereby repressing pyroptosis. The regulatory role of AMPK-mediated GSDME phosphorylation was further confirmed in AMPK knockout and GSDMET6E or GSDMET6A knock-in mice. In mouse primary cancer models, mannose administration suppressed pyroptosis in small intestine and kidney to alleviate cisplatin- or oxaliplatin-induced tissue toxicity without impairing antitumor effects. The protective effect of mannose was also verified in a small group of patients with gastrointestinal cancer who received normal chemotherapy. Our study reveals a novel mechanism whereby mannose antagonizes GSDME-mediated pyroptosis through GlcNAc-6P-mediated activation of AMPK, and suggests the utility of mannose supplementation in alleviating chemotherapy-induced side effects in clinic applications.


Assuntos
Manose , Piroptose , Humanos , Animais , Camundongos , Manose/farmacologia , Proteínas Quinases Ativadas por AMP , Gasderminas
10.
Cell Chem Biol ; 30(3): 261-277.e8, 2023 03 16.
Artigo em Inglês | MEDLINE | ID: mdl-36889311

RESUMO

Pulmonary fibrosis is a typical sequela of coronavirus disease 2019 (COVID-19), which is linked with a poor prognosis for COVID-19 patients. However, the underlying mechanism of pulmonary fibrosis induced by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is unclear. Here, we demonstrated that the nucleocapsid (N) protein of SARS-CoV-2 induced pulmonary fibrosis by activating pulmonary fibroblasts. N protein interacted with the transforming growth factor ß receptor I (TßRI), to disrupt the interaction of TßRI-FK506 Binding Protein12 (FKBP12), which led to activation of TßRI to phosphorylate Smad3 and boost expression of pro-fibrotic genes and secretion of cytokines to promote pulmonary fibrosis. Furthermore, we identified a compound, RMY-205, that bound to Smad3 to disrupt TßRI-induced Smad3 activation. The therapeutic potential of RMY-205 was strengthened in mouse models of N protein-induced pulmonary fibrosis. This study highlights a signaling pathway of pulmonary fibrosis induced by N protein and demonstrates a novel therapeutic strategy for treating pulmonary fibrosis by a compound targeting Smad3.


Assuntos
COVID-19 , Fibrose Pulmonar , Animais , Camundongos , COVID-19/complicações , Fibrose , Proteínas do Nucleocapsídeo/uso terapêutico , Fibrose Pulmonar/complicações , Fibrose Pulmonar/tratamento farmacológico , SARS-CoV-2
11.
Carcinogenesis ; 33(2): 301-11, 2012 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-22159226

RESUMO

Cisplatin is a widely used antitumor agent that induces aggressive cancer cell death via triggering cellular proteins involved in apoptosis. Here, we demonstrate that cisplatin effectively induces orphan nuclear receptor TR3 phosphorylation by activating Chk2 kinase activity and promoting cross talk between these two proteins, thereby contributing to the repression of intestinal tumorigenesis via apoptosis. Mechanistic analysis has demonstrated that Chk2-induced phosphorylation enables TR3 to bind to its response elements on the promoters of the BRE and RNF-7 genes, leading to the negative regulation of these two anti-apoptotic genes. Furthermore, the induction of apoptosis by cisplatin is mediated by TR3, and knockdown of TR3 reduces cisplatin-induced apoptosis in colon cancer cells by 27%. The role of TR3 in cisplatin chemotherapy is further clarified in mouse models. In Apc(min/+) mice, cisplatin inhibits intestinal tumorigenesis by 70% in a TR3 phosphorylation-dependent manner; however, the loss of TR3 function in Apc(min/+)/TR3(-/-) mice leads to the failure of cisplatin-induced repression of tumorigenesis. Consistently, xenografts derived from TR3 knockdown colon cancer cells are insensitive to cisplatin treatment, whereas a significant curative effect (50% inhibition) is observed in xenografts with functional TR3. Taken together, our study reveals a novel cross talk between Chk2 and TR3 and sheds light on the mechanism of cisplatin-induced apoptosis through TR3. Therefore, TR3 may be a new target of cisplatin for colon cancer therapy.


Assuntos
Apoptose/efeitos dos fármacos , Transformação Celular Neoplásica/efeitos dos fármacos , Cisplatino/farmacologia , Neoplasias Intestinais/prevenção & controle , Membro 1 do Grupo A da Subfamília 4 de Receptores Nucleares/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Animais , Antineoplásicos/farmacologia , Apoptose/genética , Linhagem Celular Transformada , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/metabolismo , Quinase do Ponto de Checagem 2 , Neoplasias do Colo/genética , Neoplasias do Colo/prevenção & controle , Técnicas de Silenciamento de Genes/métodos , Células HEK293 , Humanos , Neoplasias Intestinais/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Nus , Proteínas do Tecido Nervoso/antagonistas & inibidores , Proteínas do Tecido Nervoso/genética , Membro 1 do Grupo A da Subfamília 4 de Receptores Nucleares/genética , Fosforilação/efeitos dos fármacos , Regiões Promotoras Genéticas , Ligação Proteica , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Transplante Heterólogo/métodos
12.
Nat Metab ; 4(10): 1306-1321, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-36192599

RESUMO

Extracellular vesicles play crucial roles in intercellular communication in the tumor microenvironment. Here we demonstrate that in hepatic fibrosis, TGF-ß stimulates the palmitoylation of hexokinase 1 (HK1) in hepatic stellate cells (HSCs), which facilitates the secretion of HK1 via large extracellular vesicles in a TSG101-dependent manner. The large extracellular vesicle HK1 is hijacked by hepatocellular carcinoma (HCC) cells, leading to accelerated glycolysis and HCC progression. In HSCs, the nuclear receptor Nur77 transcriptionally activates the expression of depalmitoylase ABHD17B to inhibit HK1 palmitoylation, consequently attenuating HK1 release. However, TGF-ß-activated Akt functionally represses Nur77 by inducing Nur77 phosphorylation and degradation. We identify the small molecule PDNPA that binds Nur77 to generate steric hindrance to block Akt targeting, thereby disrupting Akt-mediated Nur77 degradation and preserving Nur77 inhibition of HK1 release. Together, this study demonstrates an overlooked function of HK1 in HCC upon its release from HSCs and highlights PDNPA as a candidate compound for inhibiting HCC progression.


Assuntos
Carcinoma Hepatocelular , Vesículas Extracelulares , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Células Estreladas do Fígado/metabolismo , Hexoquinase/metabolismo , Neoplasias Hepáticas/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proliferação de Células , Linhagem Celular Tumoral , Vesículas Extracelulares/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Receptores Citoplasmáticos e Nucleares/metabolismo , Microambiente Tumoral
13.
Nucleic Acids Res ; 37(3): 832-48, 2009 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-19095693

RESUMO

PRMT1, an arginine methyltransferase, plays an important role in numerous cellular processes. In this study, we demonstrate a feedback regulatory loop between PRMT1 and the orphan receptor TR3. Unlike another orphan receptor HNF4, TR3 is not methylated by PRMT1 although they physically interact with each other. By delaying the TR3 protein degradation, PRMT1 binding leads to the elevation of TR3 cellular protein level, thereby enhances the DNA binding and transactivation activity of TR3 in a non-methyltransferase manner. Another coactivator SRC-2 acts synergistically with PRMT1 to regulate TR3 functions. In turn, TR3 binding to the catalytic domain of PRMT1 causes an inhibition of the PRMT1 methyltransferase activity. This repression results in the functional changes in some of PRMT1 substrates, including STAT3 and Sam68. The negative regulation of PRMT1 by TR3 was further confirmed in both TR3-knockdown cells and TR3-knockout mice with the use of an agonist for TR3. Taken together, our study not only identifies a regulatory role of PRMT1, independent on methyltransferase activity, in TR3 transactivation, but also characterizes a novel function of TR3 in the repression of PRMT1 methyltransferase activity.


Assuntos
Proteínas de Ligação a DNA/metabolismo , Retroalimentação Fisiológica , Proteína-Arginina N-Metiltransferases/metabolismo , Receptores de Esteroides/metabolismo , Proteínas Repressoras/metabolismo , Animais , Linhagem Celular , Proteínas de Ligação a DNA/agonistas , Humanos , Camundongos , Camundongos Knockout , Coativador 2 de Receptor Nuclear/metabolismo , Membro 1 do Grupo A da Subfamília 4 de Receptores Nucleares , Proteína-Arginina N-Metiltransferases/antagonistas & inibidores , Receptores de Esteroides/agonistas , Proteínas Repressoras/antagonistas & inibidores
14.
Cancer Lett ; 516: 48-56, 2021 09 28.
Artigo em Inglês | MEDLINE | ID: mdl-34082025

RESUMO

Extracellular vesicles (EVs) have gained significant attention in recent decades as major mediators of intercellular communication that are involved in various essential physiological and pathological processes. They are secreted by almost all cell types and carry bioactive materials, such as proteins, lipids and nucleic acids, that can be transmitted from host cells to recipient cells, thereby eliciting phenotypic and functional alterations in the recipient cells. Recent evidence shows that EVs play essential roles in remodeling the tumor immune microenvironment (TIME). EVs derived from tumor cells and immune cells mediate mutual communication at proximal and distal sites, which determines tumor fate and antitumor therapeutic effectiveness. In this review, the current understanding of EVs and their roles in remodeling the TIME and modulating tumor-specific immunity are summarized. We mainly discuss the mutual regulation between tumor cells and tumor-infiltrating immune cells through the delivery of EVs in the TIME. We also describe the limitations of current studies and discuss directions for further research.


Assuntos
Vesículas Extracelulares/imunologia , Neoplasias/imunologia , Microambiente Tumoral/imunologia , Humanos , Linfócitos do Interstício Tumoral/imunologia
15.
Cell Res ; 31(9): 980-997, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34012073

RESUMO

Pyroptosis is a form of regulated cell death mediated by gasdermin family members, among which the function of GSDMC has not been clearly described. Herein, we demonstrate that the metabolite α-ketoglutarate (α-KG) induces pyroptosis through caspase-8-mediated cleavage of GSDMC. Treatment with DM-αKG, a cell-permeable derivative of α-KG, elevates ROS levels, which leads to oxidation of the plasma membrane-localized death receptor DR6. Oxidation of DR6 triggers its endocytosis, and then recruits both pro-caspase-8 and GSDMC to a DR6 receptosome through protein-protein interactions. The DR6 receptosome herein provides a platform for the cleavage of GSDMC by active caspase-8, thereby leading to pyroptosis. Moreover, this α-KG-induced pyroptosis could inhibit tumor growth and metastasis in mouse models. Interestingly, the efficiency of α-KG in inducing pyroptosis relies on an acidic environment in which α-KG is reduced by MDH1 and converted to L-2HG that further boosts ROS levels. Treatment with lactic acid, the end product of glycolysis, builds an improved acidic environment to facilitate more production of L-2HG, which makes the originally pyroptosis-resistant cancer cells more susceptible to α-KG-induced pyroptosis. This study not only illustrates a pyroptotic pathway linked with metabolites but also identifies an unreported principal axis extending from ROS-initiated DR6 endocytosis to caspase-8-mediated cleavage of GSDMC for potential clinical application in tumor therapy.


Assuntos
Caspase 8 , Proteínas de Ligação a DNA , Neoplasias , Piroptose , Receptores do Fator de Necrose Tumoral , Animais , Caspase 1/metabolismo , Ácidos Cetoglutáricos , Camundongos , Receptores de Morte Celular
16.
Oncogene ; 39(11): 2408-2423, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31959898

RESUMO

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related mortality worldwide. Orphan nuclear receptor Nur77, which is low expressed in HCC, functions as a tumor suppressor to suppress HCC. However, the detailed mechanism is still not well understood. Here, we demonstrate that Nur77 could inhibit HCC development via transcriptional activation of the lncRNA WAP four-disulfide core domain 21 pseudogene (WFDC21P). Nur77 binds to its response elements on the WFDC21P promoter to directly induce WFDC21P transcription, which inhibits HCC cell proliferation, tumor growth, and tumor metastasis both in vitro and in vivo. In clinical HCC samples, WFDC21P expression positively correlated with that of Nur77, and the loss of WFDC21P is associated with worse prognosis. Mechanistically, WFDC21P could inhibit glycolysis by simultaneously interacting with PFKP and PKM2, two key enzymes in glycolysis. These interactions not only abrogate the tetramer formation of PFKP to impede its catalytic activity but also prevent the nuclear translocation of PKM2 to suppress its function as a transcriptional coactivator. Cytosporone-B (Csn-B), an agonist for Nur77, could stimulate WFDC21P expression and suppress HCC in a WFDC21P-dependent manner. Therefore, our study reveals a new HCC suppressor and connects the glycolytic remodeling of HCC with the Nur77-WFDC21P-PFKP/PKM2 axis.


Assuntos
Carcinoma Hepatocelular/metabolismo , Neoplasias Hepáticas/metabolismo , Membro 1 do Grupo A da Subfamília 4 de Receptores Nucleares/metabolismo , RNA Longo não Codificante/metabolismo , Animais , Carcinogênese , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Processos de Crescimento Celular , Linhagem Celular Tumoral , Glicólise , Células Hep G2 , Xenoenxertos , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Membro 1 do Grupo A da Subfamília 4 de Receptores Nucleares/agonistas , Membro 1 do Grupo A da Subfamília 4 de Receptores Nucleares/genética , Fenilacetatos/farmacologia , Regiões Promotoras Genéticas , RNA Longo não Codificante/genética , Ativação Transcricional , Regulação para Cima
17.
Cell Rep ; 33(3): 108284, 2020 10 20.
Artigo em Inglês | MEDLINE | ID: mdl-33086070

RESUMO

The Hippo signaling pathway maintains organ size and tissue homeostasis via orchestration of cell proliferation and apoptosis. How this pathway triggers cell apoptosis remains largely unexplored. Here, we identify NR4A1 as a target of the Hippo pathway that mediates the pro-apoptotic and anti-tumor effects of the Hippo pathway whereby YAP regulates the transcription, phosphorylation, and mitochondrial localization of NR4A1. NR4A1, in turn, functions as a feedback inhibitor of YAP to promote its degradation, thereby inhibiting the function of YAP during liver regeneration and tumorigenesis. Our studies elucidate a regulatory loop between NR4A1 and YAP to coordinate Hippo signaling activity during liver regeneration and tumorigenesis and highlight NR4A1 as a marker of Hippo signaling, as well as a therapeutic target for hepatocellular carcinoma.


Assuntos
Proteínas de Ciclo Celular/metabolismo , Membro 1 do Grupo A da Subfamília 4 de Receptores Nucleares/metabolismo , Fatores de Transcrição/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Apoptose/fisiologia , Carcinogênese , Carcinoma Hepatocelular/patologia , Proteínas de Ciclo Celular/genética , Linhagem Celular Tumoral , Proliferação de Células/fisiologia , Feminino , Homeostase/fisiologia , Humanos , Neoplasias Hepáticas/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteínas Nucleares/metabolismo , Membro 1 do Grupo A da Subfamília 4 de Receptores Nucleares/genética , Fosforilação , Transdução de Sinais/efeitos dos fármacos , Transativadores/metabolismo , Fatores de Transcrição/genética , Proteínas de Sinalização YAP
18.
Nucleic Acids Res ; 35(21): 7348-59, 2007.
Artigo em Inglês | MEDLINE | ID: mdl-17962304

RESUMO

p300 regulates the transcriptional activity of a variety of transcription factors by forming an activation complex and/or promoting histone acetylation. Here, we show a unique characteristic of orphan receptor TR3 in negatively regulating the function of p300. TR3 was found to interact with p300 and inhibited the acetylation of transcription factors induced by p300, resulting in the repression of their transcriptional activity. Further analysis revealed that both a conserved transcriptional adapter motif (TRAM) in p300 and a specific sequence FLELFIL in TR3 were critical for their interaction. TR3 binding completely covered the histone acetyltransferase (HAT) domain of p300 and resulted in suppression of the HAT activity, as the p300-induced histone H3 acetylation and transcription were inhibited with the presence TR3. Furthermore, an agonist of TR3, a natural octaketide isolated from Dothiorella sp. HTF3 of an endophytical fungus, was shown to be a potent compound for inhibiting p300 HAT activity (IC(50) = 1.5 microg/ml) in vivo. More importantly, this agonist could repress the transcriptional activity of transcription factors, and proliferation of cancer cells. Taken together, our results not only delineate a novel transcriptional repressor function for TR3, but also reveal its modulation on p300 HAT activity as the underlying mechanism.


Assuntos
Receptores de Esteroides/metabolismo , Receptores dos Hormônios Tireóideos/metabolismo , Proteínas Repressoras/metabolismo , Fatores de Transcrição de p300-CBP/antagonistas & inibidores , Acetilação , Sequência de Aminoácidos , Sítios de Ligação , Linhagem Celular , Regulação para Baixo , Regulação da Expressão Gênica , Humanos , Membro 1 do Grupo A da Subfamília 4 de Receptores Nucleares , Receptores de Esteroides/agonistas , Receptores de Esteroides/química , Receptores dos Hormônios Tireóideos/agonistas , Receptores dos Hormônios Tireóideos/química , Proteínas Repressoras/agonistas , Proteínas Repressoras/química , Fatores de Transcrição de p300-CBP/química , Fatores de Transcrição de p300-CBP/metabolismo
19.
Carcinogenesis ; 29(11): 2078-88, 2008 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-18713840

RESUMO

Acutely transforming retrovirus AKT8 in rodent T cell lymphoma (Akt) phosphorylates and regulates the function of many cellular proteins involved in processes such as metabolism, apoptosis and proliferation. However, the precise mechanisms by which Akt promotes cell survival and inhibits apoptosis have been characterized in part only. TR3, an orphan receptor, functions as a transcription factor that can both positively or negatively regulate gene expression. We have reported previously that the translocation of TR3 from the nucleus to the mitochondria can elicit a proapoptotic effect in gastric cancer cells. In our present study, we demonstrate that Akt phosphorylates cytoplasmic TR3 through its physical interaction with the N-terminus of TR3. When coexpressed with Akt, TR3 mitochondrial targeting was blocked and this protein adopted a diffuse expression pattern in the cytoplasm. Moreover, Akt displayed an ability to disrupt the interaction of TR3 with Bcl-2, which is thought to be a critical requirement for mitochondrial TR3 to elicit apoptosis. Consistently, insulin was also found to induce the phosphorylation of TR3 and abolish 12-O-tetradecanoylphorbol-13-acetate-induced mitochondrial localization, which was dependent upon the activation of the phophatidylinositol-3-OH-kinase-Akt signaling pathway. Taken together, our current data demonstrate a unique role for Akt in inhibiting TR3 functions that are not related to transcriptional activity but that correlate with the regulation of its mitochondrial association. This may represent a novel signal pathway by which Akt exerts its antiapoptotic effects in gastric cancer cells, i.e. by regulating the phosphorylation and redistribution of orphan receptors.


Assuntos
Mitocôndrias/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptores de Esteroides/metabolismo , Receptores dos Hormônios Tireóideos/metabolismo , Apoptose , Sequência de Bases , Sítios de Ligação , Western Blotting , Linhagem Celular Tumoral , Citocromos c/metabolismo , Citoplasma/metabolismo , Primers do DNA , Imunofluorescência , Humanos , Imunoprecipitação , Membro 1 do Grupo A da Subfamília 4 de Receptores Nucleares , Fosforilação , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Receptores de Esteroides/química , Receptores dos Hormônios Tireóideos/química
20.
Mol Endocrinol ; 21(12): 2877-89, 2007 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-17761950

RESUMO

Acetylation modification regulates the functions of histone and nonhistone proteins, including transcriptional activity, protein interaction, and subcellular localization. Although many nuclear receptors have been shown to be modified by acetylation, whether retinoid X receptors (RXRs) are acetylated and how the acetylation is regulated remains unknown. Here, we provide the first evidence of RXRalpha acetylation by p300 on lysine 145. Acetylation of RXRalpha by p300 facilitated its DNA binding and subsequently increased its transcriptional activity. Furthermore, we discovered that TR3, an orphan receptor, exerted a negative regulation on p300-induced RXRalpha acetylation. TR3 significantly reduced the p300-induced RXRalpha acetylation and transcriptional activity, and such inhibition required the interaction of TR3 with RXRalpha. Binding of TR3 to RXRalpha resulted in the sequestration of RXRalpha from p300. 9-cis retinoic acid, a ligand for RXRalpha, enhanced the association of RXRalpha with TR3, rather than acetylation of RXRalpha by p300. Biological function analysis revealed that the mitogenic activity of RXRalpha stimulated by p300 was acetylation dependent and could be repressed by TR3. Upon the treatment of 9-cis retinoic acid, RXRalpha was translocated with TR3 from the nucleus to the mitochondria, and apoptosis was induced. Taken together, our data demonstrate the distinct regulatory mechanisms of p300 and TR3 on RXRalpha acetylation and reveal a previously unrecognized role for orphan receptor in the transcriptional control of retinoid receptors.


Assuntos
Proteína p300 Associada a E1A/metabolismo , Receptores de Esteroides/metabolismo , Receptores dos Hormônios Tireóideos/metabolismo , Receptores X de Retinoides/metabolismo , Acetilação , Alitretinoína , Apoptose , Linhagem Celular , DNA/metabolismo , Humanos , Lisina/genética , Lisina/metabolismo , Membro 1 do Grupo A da Subfamília 4 de Receptores Nucleares , Ligação Proteica , Transporte Proteico , Receptores de Esteroides/genética , Receptores dos Hormônios Tireóideos/genética , Receptores X de Retinoides/genética , Transcrição Gênica/efeitos dos fármacos , Transcrição Gênica/genética , Tretinoína/farmacologia
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA