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1.
Int J Mol Sci ; 22(2)2021 Jan 19.
Artigo em Inglês | MEDLINE | ID: mdl-33477764

RESUMO

The Hippo signaling pathway plays a key role in regulating organ size and tissue homeostasis. Hippo and two of its main effectors, yes-associated protein (YAP) and WWTR1 (WW domain-containing transcription regulator 1, commonly listed as TAZ), play critical roles in angiogenesis. This study investigated the role of the Hippo signaling pathway in the pathogenesis of rosacea. We performed immunohistochemical analyses to compare the expression levels of YAP and TAZ between rosacea skin and normal skin in humans. Furthermore, we used a rosacea-like BALB/c mouse model induced by LL-37 injections to determine the roles of YAP and TAZ in rosacea in vivo. We found that the expression levels of YAP and TAZ were upregulated in patients with rosacea. In the rosacea-like mouse model, we observed that the clinical features of rosacea, including telangiectasia and erythema, improved after the injection of a YAP/TAZ inhibitor. Additionally, treatment with a YAP/TAZ inhibitor reduced the expression levels of YAP and TAZ and diminished vascular endothelial growth factor (VEGF) immunoreactivity in the rosacea-like mouse model. Our findings suggest that YAP/TAZ inhibitors can attenuate angiogenesis associated with the pathogenesis of rosacea and that both YAP and TAZ are potential therapeutic targets for patients with rosacea.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/antagonistas & inibidores , Proteínas de Ciclo Celular/antagonistas & inibidores , Rosácea/tratamento farmacológico , Transativadores/antagonistas & inibidores , Fator A de Crescimento do Endotélio Vascular/genética , Proteínas Adaptadoras de Transdução de Sinal/genética , Animais , Proteínas de Ciclo Celular/genética , Modelos Animais de Doenças , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Camundongos , Proteínas Serina-Treonina Quinases/genética , Rosácea/genética , Rosácea/patologia , Transdução de Sinais/efeitos dos fármacos , Pele/efeitos dos fármacos , Pele/patologia , Transativadores/genética
2.
Cell Prolif ; 54(2): e12976, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33393124

RESUMO

BACKGROUND: In mammals, early pregnancy is a critical vulnerable period during which complications may arise, including pregnancy failure. Establishment of a maternal endometrial acceptance phenotype is a prerequisite for semiheterogeneous embryo implantation, comprising the rate-limiting step of early pregnancy. METHODS: Confocal fluorescence, immunohistochemistry and western blot for nuclear and cytoplasmic protein were used to examine the activation of yes-associated protein (YAP) in uterine tissue and primary endometrial cells. The target binding between miR16a and YAP was verified by dual-luciferase reporter gene assay. The mouse pregnancy model and pseudopregnancy model were used to investigate the role of YAP in the maternal uterus during early pregnancy in vivo. RESULTS: We showed that YAP translocates into the nucleus in the endometrium of cattle and mice during early pregnancy. Mechanistically, YAP acts as a mediator of ECM rigidity and cell density, which requires the actomyosin cytoskeleton and is partially dependent on the Hippo pathway. Furthermore, we found that the soluble factor IFNτ, which is a ruminant pregnancy recognition factor, also induced activation of YAP by reducing the expression of miR-16a. CONCLUSIONS: This study revealed that activation of YAP is necessary for early pregnancy in bovines because it induced cell proliferation and established an immunosuppressive local environment that allowed conceptus implantation into the uterine epithelium.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Proteínas de Ciclo Celular/metabolismo , Endométrio/metabolismo , Matriz Extracelular/metabolismo , Interferon Tipo I/metabolismo , Proteínas da Gravidez/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/antagonistas & inibidores , Proteínas Adaptadoras de Transdução de Sinal/genética , Animais , Antagomirs/metabolismo , Bovinos , Proteínas de Ciclo Celular/antagonistas & inibidores , Proteínas de Ciclo Celular/genética , Endométrio/citologia , Molécula de Adesão da Célula Epitelial/metabolismo , Feminino , Expressão Gênica/efeitos dos fármacos , Interferon Tipo I/farmacologia , Masculino , Camundongos , MicroRNAs/antagonistas & inibidores , MicroRNAs/genética , MicroRNAs/metabolismo , Proteínas Musculares/metabolismo , Gravidez , Proteínas da Gravidez/farmacologia , Proteínas Serina-Treonina Quinases/metabolismo , Interferência de RNA , RNA Interferente Pequeno/metabolismo , Transdução de Sinais , Útero/metabolismo , Útero/patologia
3.
Methods Mol Biol ; 2217: 301-311, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33215388

RESUMO

In endothelial cells (ECs), the onset of apicobasal polarity is primarily regulated by the interaction of integrins with the surrounding extracellular matrix (ECM). ECs secrete and polymerize fibronectin (FN), a unique, permissive substrate that allows for vascular morphogenesis and lumen formation. We previously identified a signaling pathway that, under the control of the adhesion site adaptor protein PPFIA1, integrates the polarized secretion of freshly synthesized FN with the recycling of conformationally active α5ß1 integrin, the main FN receptor in ECs. To characterize the functional role of PPFIA1-dependent signaling in ECs, we set up a Transwell-based assay to quantify the polarized secretion of ECM proteins. To this aim, we allowed ECs to form a confluent monolayer on the Transwell membrane and checked its integrity by measuring transendothelial electric resistance and controlling the stability of tight junctions over time by fluorescent confocal microscope analysis. Finally, we quantified apical and basolateral FN secretion in control and PPFIA1-silenced EC culture medium by western blot analysis coupled to spike-in normalization.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Células Endoteliais/metabolismo , Matriz Extracelular/metabolismo , Fibronectinas/genética , Integrina alfa5beta1/genética , Junções Íntimas/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/antagonistas & inibidores , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Transporte Biológico , Polaridade Celular , Cultura em Câmaras de Difusão , Células Endoteliais/ultraestrutura , Matriz Extracelular/ultraestrutura , Fibronectinas/metabolismo , Regulação da Expressão Gênica , Complexo de Golgi/metabolismo , Complexo de Golgi/ultraestrutura , Humanos , Integrina alfa5beta1/metabolismo , Microscopia de Fluorescência/métodos , Cultura Primária de Células , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Transdução de Sinais , Junções Íntimas/ultraestrutura
4.
Mol Pharmacol ; 99(1): 1-16, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33130557

RESUMO

Aberrant activation of Wnt/ß-catenin axis occurs in several gastrointestinal malignancies due to inactivating mutations of adenomatous polyposis coli (in colorectal cancer) or activating mutations of ß-catenin itself [in hepatocellular carcinoma (HCC)]. These lead to ß-catenin stabilization, increase in ß-catenin/T-cell factor (TCF)-mediated transcriptional activation, and target gene expression, many of which are involved in tumor progression. While studying pharmaceutical agents that can target ß-catenin in cancer cells, we observed that the plant compound berberine (BBR), a potent activator of AMP-activated protein kinase (AMPK), can reduce ß-catenin expression and downstream signaling in HCC cells in a dose-dependent manner. More in-depth analyses to understand the mechanism revealed that BBR-induced reduction of ß-catenin occurs independently of AMPK activation and does not involve transcriptional or post-translational mechanisms. Pretreatment with protein synthesis inhibitor cycloheximide antagonized BBR-induced ß-catenin reduction, suggesting that BBR affects ß-catenin translation. BBR treatment also antagonized mammalian target of rapamycin (mTOR) activity and was associated with increased recruitment of eukaryotic translation initiation factor 4E-binding protein (4E-BP) 1 in the translational complex, which was revealed by 7-methyl-cap-binding assays, suggesting inhibition of cap-dependent translation. Interestingly, knocking down 4E-BP1 and 4E-BP2 significantly attenuated BBR-induced reduction of ß-catenin levels and expression of its downstream target genes. Moreover, cells with 4E-BP knockdown were resistant to BBR-induced cell death and were resensitized to BBR after pharmacological inhibition of ß-catenin. Our findings indicate that BBR antagonizes ß-catenin pathway by inhibiting ß-catenin translation and mTOR activity and thereby reduces HCC cell survival. These also suggest that BBR could be used for targeting HCCs that express mutated/activated ß-catenin variants that are currently undruggable. SIGNIFICANCE STATEMENT: ß-catenin signaling is aberrantly activated in different gastrointestinal cancers, including hepatocellular carcinoma, which is currently undruggable. In this study we describe a novel mechanism of targeting ß-catenin translation via utilizing a plant compound, berberine. Our findings provide a new avenue of targeting ß-catenin axis in cancer, which can be utilized toward the designing of effective therapeutic strategies to combat ß-catenin-dependent cancers.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Berberina/farmacologia , Carcinoma Hepatocelular/metabolismo , Proteínas de Ciclo Celular/metabolismo , Fatores de Iniciação em Eucariotos/metabolismo , Neoplasias Hepáticas/metabolismo , beta Catenina/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/antagonistas & inibidores , Proteínas Adaptadoras de Transdução de Sinal/genética , Carcinoma Hepatocelular/genética , Proteínas de Ciclo Celular/antagonistas & inibidores , Proteínas de Ciclo Celular/genética , Fatores de Iniciação em Eucariotos/antagonistas & inibidores , Fatores de Iniciação em Eucariotos/genética , Células HEK293 , Células Hep G2 , Humanos , Neoplasias Hepáticas/genética , Biossíntese de Proteínas/efeitos dos fármacos , Biossíntese de Proteínas/fisiologia , beta Catenina/antagonistas & inibidores , beta Catenina/genética
5.
Nat Commun ; 11(1): 5357, 2020 10 23.
Artigo em Inglês | MEDLINE | ID: mdl-33097721

RESUMO

Low-density lipoprotein receptor-related protein 6 (LRP6) is a coreceptor of the ß-catenin-dependent Wnt signaling pathway. The LRP6 ectodomain binds Wnt proteins, as well as Wnt inhibitors such as sclerostin (SOST), which negatively regulates Wnt signaling in osteocytes. Although LRP6 ectodomain 1 (E1) is known to interact with SOST, several unresolved questions remain, such as the reason why SOST binds to LRP6 E1E2 with higher affinity than to the E1 domain alone. Here, we present the crystal structure of the LRP6 E1E2-SOST complex with two interaction sites in tandem. The unexpected additional binding site was identified between the C-terminus of SOST and the LRP6 E2 domain. This interaction was confirmed by in vitro binding and cell-based signaling assays. Its functional significance was further demonstrated in vivo using Xenopus laevis embryos. Our results provide insights into the inhibitory mechanism of SOST on Wnt signaling.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/antagonistas & inibidores , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Proteína-6 Relacionada a Receptor de Lipoproteína de Baixa Densidade/metabolismo , Proteínas Wnt/metabolismo , Via de Sinalização Wnt/efeitos dos fármacos , Proteínas Adaptadoras de Transdução de Sinal/química , Animais , Sítios de Ligação , Cristalografia por Raios X , Feminino , Células HEK293 , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/química , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Proteína-6 Relacionada a Receptor de Lipoproteína de Baixa Densidade/química , Modelos Moleculares , Peptídeos/metabolismo , Ligação Proteica , Conformação Proteica , Transcriptoma , Xenopus laevis/embriologia , Xenopus laevis/metabolismo , beta Catenina/metabolismo
6.
Inflamm Res ; 69(12): 1215-1234, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33044562

RESUMO

OBJECTIVE AND DESIGN: Macrophages exhibit strong phenotypic plasticity and can mediate renal inflammation by polarizing into an M1 phenotype. They play a pivotal role in diabetic nephropathy (DN). Here, we have investigated the regulatory role of transforming growth factor ß-activated kinase 1-binding protein 1 (TAB1) in glycolysis and activation of macrophages during DN. METHODS: TAB1 was inhibited using siRNA in high glucose (HG)-stimulated bone marrow-derived macrophages (BMMs) and lentiviral vector-mediated TAB1 knockdown was used in streptozotocin (STZ)-induced diabetic mice. Western blotting, flow cytometry, qRT-PCR, ELISA, PAS staining and immunohistochemical staining were used for assessment of TAB1/nuclear factor-κB (NF-κB)/hypoxia-inducible factor-1α (HIF-1α), iNOS, glycolysis, inflammation and the clinical and pathological manifestations of diabetic nephropathy. RESULTS: We found that TAB1/NF-κB/HIF-1α, iNOS and glycolysis were up-regulated in BMMs under HG conditions, leading to release of further inflammatory factors, Downregulation of TAB1 could inhibit glycolysis/polarization of macrophages and inflammation in vivo and in vitro. Furthermore, albuminuria, the tubulointerstitial damage index and glomerular mesangial expansion index of STZ-induced diabetic nephropathy mice were decreased by TAB1 knockdown. CONCLUSIONS: Our results suggest that the TAB1/NF-κB/HIF-1α signaling pathway regulates glycolysis and activation of macrophages in DN.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Neuropatias Diabéticas/genética , Neuropatias Diabéticas/metabolismo , Glicólise/genética , Ativação de Macrófagos/genética , Proteínas Adaptadoras de Transdução de Sinal/antagonistas & inibidores , Albuminúria/tratamento farmacológico , Albuminúria/patologia , Animais , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/metabolismo , Técnicas de Silenciamento de Genes , Subunidade alfa do Fator 1 Induzível por Hipóxia/efeitos dos fármacos , Células Mesangiais/patologia , Camundongos , Camundongos Endogâmicos C57BL , NF-kappa B/efeitos dos fármacos , Nefrite Intersticial/patologia , Óxido Nítrico Sintase Tipo II/efeitos dos fármacos , RNA Interferente Pequeno/farmacologia
7.
Nat Commun ; 11(1): 4766, 2020 09 21.
Artigo em Inglês | MEDLINE | ID: mdl-32958778

RESUMO

Germline telomere maintenance defects are associated with an increased incidence of inflammatory diseases in humans, yet whether and how telomere dysfunction causes inflammation are not known. Here, we show that telomere dysfunction drives pATM/c-ABL-mediated activation of the YAP1 transcription factor, up-regulating the major pro-inflammatory factor, pro-IL-18. The colonic microbiome stimulates cytosolic receptors activating caspase-1 which cleaves pro-IL-18 into mature IL-18, leading to recruitment of interferon (IFN)-γ-secreting T cells and intestinal inflammation. Correspondingly, patients with germline telomere maintenance defects exhibit DNA damage (γH2AX) signaling together with elevated YAP1 and IL-18 expression. In mice with telomere dysfunction, telomerase reactivation in the intestinal epithelium or pharmacological inhibition of ATM, YAP1, or caspase-1 as well as antibiotic treatment, dramatically reduces IL-18 and intestinal inflammation. Thus, telomere dysfunction-induced activation of the ATM-YAP1-pro-IL-18 pathway in epithelium is a key instigator of tissue inflammation.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Proteínas de Ciclo Celular/metabolismo , Inflamação/patologia , Telômero/patologia , Proteínas Adaptadoras de Transdução de Sinal/antagonistas & inibidores , Proteínas Adaptadoras de Transdução de Sinal/genética , Animais , Antibacterianos/uso terapêutico , Proteínas Mutadas de Ataxia Telangiectasia/antagonistas & inibidores , Proteínas Mutadas de Ataxia Telangiectasia/metabolismo , Caspase 1/metabolismo , Proteínas de Ciclo Celular/antagonistas & inibidores , Proteínas de Ciclo Celular/genética , Criança , Colo/metabolismo , Colo/microbiologia , Colo/patologia , Gastroenteropatias/patologia , Microbioma Gastrointestinal/efeitos dos fármacos , Microbioma Gastrointestinal/fisiologia , Humanos , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Inflamação/microbiologia , Interleucina-18/genética , Interleucina-18/metabolismo , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patologia , Camundongos , Camundongos Mutantes , Fosforilação , Precursores de Proteínas/genética , Precursores de Proteínas/metabolismo , Transdução de Sinais , Telomerase/genética , Telomerase/metabolismo
8.
Eur J Med Chem ; 200: 112338, 2020 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-32497960

RESUMO

Histone modifying proteins, specifically histone deacetylases (HDACs) and bromodomains, have emerged as novel promising targets for anticancer therapy. In the current work, based on available crystal structures and docking studies, we designed dual inhibitors of both HDAC6/8 and the bromodomain and PHD finger containing protein 1 (BRPF1). Biochemical and biophysical tests showed that compounds 23a,b and 37 are nanomolar inhibitors of both target proteins. Detailed structure-activity relationships were deduced for the synthesized inhibitors which were supported by extensive docking and molecular dynamics studies. Cellular testing in acute myeloid leukemia (AML) cells showed only a weak effect, most probably because of the poor permeability of the inhibitors. We also aimed to analyse the target engagement and the cellular activity of the novel inhibitors by determining the protein acetylation levels in cells by western blotting (tubulin vs histone acetylation), and by assessing their effects on various cancer cell lines.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/antagonistas & inibidores , Antineoplásicos/síntese química , Proteínas de Ligação a DNA/antagonistas & inibidores , Desenho de Fármacos , Desacetilase 6 de Histona/antagonistas & inibidores , Proteínas Repressoras/antagonistas & inibidores , Acetilação/efeitos dos fármacos , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Inibidores de Histona Desacetilases/síntese química , Inibidores de Histona Desacetilases/farmacologia , Histona Desacetilases , Humanos , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/patologia , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Relação Estrutura-Atividade
9.
Sci Rep ; 10(1): 8834, 2020 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-32483202

RESUMO

Here we investigated the roles of Rab27a, a player in exosome release, and TRAF3IP2, an inflammatory mediator, in development and metastasis of breast cancer (BC) in vivo. Knockdown (KD) of Rab27a (MDAKDRab27a) or TRAF3IP2 (MDAKDTRAF3IP2) in triple negative MDA-MB231 cells reduced tumor growth by 70-97% compared to wild-type tumors (MDAw). While metastasis was detected in MDAw-injected animals, none was detected in MDAKDRab27a- or MDAKDTRAF3IP2-injected animals. Interestingly, micrometastasis was detected only in the MDAKDRab27a-injected group. In addition to inhibiting tumor growth and metastasis, silencing TRAF3IP2 disrupted inter-cellular inflammatory mediator-mediated communication with mesenchymal stem cells (MSCs) injected into contralateral mammary gland, evidenced by the lack of tumor growth at MSC-injected site. Of translational significance, treatment of pre-formed MDAw-tumors with a lentiviral-TRAF3IP2-shRNA not only regressed their size, but also prevented metastasis. These results demonstrate that while silencing Rab27a and TRAF3IP2 each inhibited tumor growth and metastasis, silencing TRAF3IP2 is more effective; targeting TRAF3IP2 inhibited tumor formation, regressed preformed tumors, and prevented both macro- and micrometastasis. Silencing TRAF3IP2 also blocked interaction between tumor cells and MSCs injected into the contralateral gland, as evidenced by the lack of tumor formation on MSCs injected site. These results identify TRAF3IP2 as a novel therapeutic target in BC.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Neoplasias da Mama/tratamento farmacológico , RNA Interferente Pequeno/uso terapêutico , Proteínas Adaptadoras de Transdução de Sinal/antagonistas & inibidores , Proteínas Adaptadoras de Transdução de Sinal/genética , Animais , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Técnicas de Cocultura , Citocinas/metabolismo , Exossomos/metabolismo , Feminino , Regulação da Expressão Gênica , Humanos , Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais/citologia , Células-Tronco Mesenquimais/metabolismo , Camundongos , Camundongos Nus , Metástase Neoplásica , Interferência de RNA , RNA Interferente Pequeno/metabolismo , Transplante Heterólogo , Proteínas rab27 de Ligação ao GTP/antagonistas & inibidores , Proteínas rab27 de Ligação ao GTP/genética , Proteínas rab27 de Ligação ao GTP/metabolismo
10.
Cancer Res ; 80(14): 3046-3056, 2020 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-32354737

RESUMO

Rhabdomyosarcoma is the most common childhood soft-tissue sarcoma, yet patients with metastatic or recurrent disease continue to do poorly, indicating a need for new treatments. The SRC family tyrosine kinase YES1 is upregulated in rhabdomyosarcoma and is necessary for growth, but clinical trials using single agent dasatinib, a SRC family kinase inhibitor, have failed in sarcomas. YAP1 (YES-associated protein) is highly expressed in rhabdomyosarcoma, driving growth and survival when the upstream Hippo tumor suppressor pathway is silenced, but efforts to pharmacologically inhibit YAP1 have been unsuccessful. Here we demonstrate that treatment of rhabdomyosarcoma with DNA methyltransferase inhibitor (DNMTi) upregulates Hippo activators RASSF1 and RASSF5 by promoter demethylation, activating canonical Hippo signaling and increasing inactivation of YAP1 by phosphorylation. Treatment with DNMTi decreased rhabdomyosarcoma cell growth and increased apoptosis and differentiation, an effect partially rescued by expression of constitutively active YAP (S127A), suggesting the effects of DNMTi treatment are, in part, due to Hippo-dependent inhibition of YAP1. In addition, YES1 and YAP1 interacted in the nucleus of rhabdomyosarcoma cells, and genetic or pharmacologic suppression of YES1 resulted in cytoplasmic retention of YAP1 and decreased YAP1 target gene expression, suggesting YES1 regulates YAP1 in a Hippo-independent manner. Combined treatment with DNMTi and dasatinib targeted both Hippo-dependent and Hippo-independent regulation of YAP1, ablating rhabdomyosarcoma cell growth in vitro and trending toward decreased tumor growth in vivo. These results show that the mechanisms regulating YAP1 in rhabdomyosarcoma can be inhibited by combinatorial therapy of DNMTi and dasatinib, laying the groundwork for future clinical investigations. SIGNIFICANCE: This study elucidates the signaling pathways that regulate the oncogenic protein YAP1 and identifies a combination therapy to target these pathways in the childhood tumor rhabdomyosarcoma.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/antagonistas & inibidores , Azacitidina/análogos & derivados , Terapia de Alvo Molecular , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Rabdomiossarcoma/tratamento farmacológico , Fatores de Transcrição/antagonistas & inibidores , Animais , Antineoplásicos/farmacologia , Apoptose , Azacitidina/farmacologia , Proliferação de Células , Criança , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Camundongos , Camundongos SCID , Rabdomiossarcoma/metabolismo , Rabdomiossarcoma/patologia , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
11.
Biochem Pharmacol ; 177: 113992, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32335141

RESUMO

IL-17A combined with TNF-α plays a vital role in inflammatory response and interference of the synergistic effect is an effective strategy for treating inflammatory diseases. Ellipticine, a natural alkaloid, has biological activities on anti-tumor and anti-HIV. However, it is still unknown whether ellipticine can inhibit IL-17A and TNF-α-mediated signaling and has treatment effect on PALI. Here, we reported that ellipticine significantly inhibited the production of pro-inflammatory cytokines and chemokines in pulmonary epithelial cell BEAS-2B treated with IL-17A and TNF-α, but not IL-17A or TNF-α alone. Meanwhile, ellipticine attenuated NF-κB and MAPKs activation in response to IL-17A and TNF-α treatment, inhibited Act1 and TRAF6-mediated NF-κB activation, and blocked the interaction of Act1 with TRAF6. Furthermore, we found that ellipticine significantly alleviated CAE and LPS-induced SAP/PALI. Ellipticine treatment dramatically reduced inflammatory cells infiltration, MPO activity, serum amylase and lipase activity and the protein concentration of BALF. Collectively, our findings indicate that ellipticine inhibits the synergistic effect of IL-17A and TNF-α by targeting on Act1 and TRAF6 interaction and is a potential therapeutic agent for the treatment of SAP/PALI.


Assuntos
Lesão Pulmonar Aguda/tratamento farmacológico , Anti-Inflamatórios/farmacologia , Elipticinas/farmacologia , Interleucina-17/antagonistas & inibidores , Pancreatite/tratamento farmacológico , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Lesão Pulmonar Aguda/induzido quimicamente , Lesão Pulmonar Aguda/complicações , Lesão Pulmonar Aguda/genética , Proteínas Adaptadoras de Transdução de Sinal/antagonistas & inibidores , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Amilases/antagonistas & inibidores , Amilases/genética , Amilases/metabolismo , Animais , Linhagem Celular Transformada , Ceruletídeo/administração & dosagem , Modelos Animais de Doenças , Células Epiteliais/citologia , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Regulação da Expressão Gênica , Células HEK293 , Humanos , Interleucina-17/farmacologia , Lipase/antagonistas & inibidores , Lipase/genética , Lipase/metabolismo , Lipopolissacarídeos/administração & dosagem , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Proteínas Quinases Ativadas por Mitógeno/antagonistas & inibidores , Proteínas Quinases Ativadas por Mitógeno/genética , Proteínas Quinases Ativadas por Mitógeno/metabolismo , NF-kappa B/antagonistas & inibidores , NF-kappa B/genética , NF-kappa B/metabolismo , Pancreatite/induzido quimicamente , Pancreatite/complicações , Pancreatite/genética , Peroxidase/antagonistas & inibidores , Peroxidase/genética , Peroxidase/metabolismo , Transdução de Sinais , Fator 6 Associado a Receptor de TNF/antagonistas & inibidores , Fator 6 Associado a Receptor de TNF/genética , Fator 6 Associado a Receptor de TNF/metabolismo , Fator de Necrose Tumoral alfa/farmacologia
12.
PLoS One ; 15(3): e0229272, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32119704

RESUMO

BACKGROUND AND AIMS: Radiotherapy is one of the major remedies for the treatment of cancer, including nasopharyngeal carcinoma (NPC). Radioresistance occurs very often in target cells that is a large drawback in cancer treated with radiotherapy. Livin involves the over-growth of cancer cells. This study aims to investigate the role of livin in the radioresistance formation in NPC cells. METHODS: NPC cell lines were exposed to small doses of irradiation to establish a cell model of radioresistance, in which the role of livin in the development of radioresistance was evaluated. RESULTS: The expression of livin was observed in NPC cells, which was significantly increased after exposing to small doses of irradiation. A negative correlation was detected between livin and Fas expression in NPC cells. Livin formed a complex with heat shock factor-1 (HSF1, the transcription factor of Fas) in NPC cells after irradiation, which sped up ubiquitination of HSF1. Livin was involved in suppressing Fas expression in NPC cells with radioresistance. Exposure to livin inhibitors prevented radioresistance development and overcame the established radioresistance in NPC cells. CONCLUSIONS: Livin expression in NPC cells plays a critical role in the development of radioresistance. Depletion of livin increases the sensitiveness of NPC cells to irradiation. Target therapy against livin may have the translational potential for the treatment of NPC.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Proteínas Inibidoras de Apoptose/genética , Proteínas Inibidoras de Apoptose/metabolismo , Carcinoma Nasofaríngeo/metabolismo , Neoplasias Nasofaríngeas/metabolismo , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Tolerância a Radiação , Regulação para Cima , Proteínas Adaptadoras de Transdução de Sinal/antagonistas & inibidores , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/efeitos da radiação , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos da radiação , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos da radiação , Fatores de Transcrição de Choque Térmico/metabolismo , Humanos , Proteínas Inibidoras de Apoptose/antagonistas & inibidores , Carcinoma Nasofaríngeo/genética , Carcinoma Nasofaríngeo/radioterapia , Neoplasias Nasofaríngeas/genética , Neoplasias Nasofaríngeas/radioterapia , Proteínas de Neoplasias/antagonistas & inibidores , Peptídeos/farmacologia , Tolerância a Radiação/efeitos dos fármacos , Transdução de Sinais , Ubiquitinação , Regulação para Cima/efeitos dos fármacos , Receptor fas/metabolismo
13.
J Med Chem ; 63(13): 6648-6676, 2020 07 09.
Artigo em Inglês | MEDLINE | ID: mdl-32130004

RESUMO

Many patients with multiple myeloma (MM) initially respond to treatment with modern combination regimens including immunomodulatory agents (lenalidomide and pomalidomide) and proteasome inhibitors. However, some patients lack an initial response to therapy (i.e., are refractory), and although the mean survival of MM patients has more than doubled in recent years, most patients will eventually relapse. To address this need, we explored the potential of novel cereblon E3 ligase modulators (CELMoDs) for the treatment of patients with relapsed or refractory multiple myeloma (RRMM). We found that optimization beyond potency of degradation, including degradation efficiency and kinetics, could provide efficacy in a lenalidomide-resistant setting. Guided by both phenotypic and protein degradation data, we describe a series of CELMoDs for the treatment of RRMM, culminating in the discovery of CC-92480, a novel protein degrader and the first CELMoD to enter clinical development that was specifically designed for efficient and rapid protein degradation kinetics.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Antineoplásicos/farmacologia , Mieloma Múltiplo/tratamento farmacológico , Ubiquitina-Proteína Ligases/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/antagonistas & inibidores , Animais , Antineoplásicos/química , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Feminino , Humanos , Concentração Inibidora 50 , Camundongos , Mieloma Múltiplo/patologia , Recidiva , Estereoisomerismo , Falha de Tratamento , Ubiquitina-Proteína Ligases/antagonistas & inibidores , Ensaios Antitumorais Modelo de Xenoenxerto
14.
Phytomedicine ; 69: 153210, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32217447

RESUMO

BACKGROUND: More than 80% of advanced prostate cancer (PCa) cases have bone metastasis, with a 5-year survival rate of 25%. Previously, we reported that GRT, a standardized, pharmaceutical-grade aspalathin-rich extract (12.78 g aspalathin/100 g extract), prepared from green rooibos produced from the leaves and fine stems of Aspalathus linearis, inhibits the proliferation of PCa cells, meriting this investigation to determine if GRT can suppress the migration and invasion of castration-resistant prostate cancer (CRPC) cells. PURPOSE: In the present study, we investigated whether GRT extract can interfere with the migration and invasion of human CRPC cells. METHODS: Transwell assays were used to explore the effects of GRT on the migration and invasion of CRPC cells. Micro-Western Array (MWA) and Western blot analysis were carried out to unravel the underlying molecular mechanism(s). RESULTS: Treatment with 25-100 µg/ml GRT suppressed the migration and invasion of LNCaP C4-2B and 22Rv1 CRPC cells. MWA and Western blot analysis indicated that GRT treatment suppressed the protein level of yes-associated protein (YAP), macrophage stimulating 1 protein (MST1), phospho-MST1/phospho-MST2 T183/T180, and paxillin, but increased the abundance of E-cadherin. Over-expression of YAP rescued the suppressive effects of GRT on migration and invasion of CRPC cells. Treatment with the major flavonoid of GRT - the C-glucosyl dihydrochalcone, aspalathin - at a concentration of 75-100 µg/ml also reduced the migration and invasion of CRPC cells, and the inhibition was partially rescued by YAP over-expression. CONCLUSIONS: GRT treatment suppresses the migration and invasion of CRPC cells via inhibition of YAP signaling and paxillin.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Aspalathus/química , Chalconas/farmacologia , Extratos Vegetais/farmacologia , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Proteínas Adaptadoras de Transdução de Sinal/antagonistas & inibidores , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Antineoplásicos Fitogênicos/química , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Humanos , Masculino , Paxilina/metabolismo , Extratos Vegetais/química , Neoplasias de Próstata Resistentes à Castração/patologia , Fatores de Transcrição/antagonistas & inibidores , Fatores de Transcrição/metabolismo
15.
Proc Natl Acad Sci U S A ; 117(10): 5260-5268, 2020 03 10.
Artigo em Inglês | MEDLINE | ID: mdl-32094196

RESUMO

A critical problem in the fight against bacterial infection is the rising rates of resistance and the lack of new antibiotics. The discovery of new targets or new antibacterial mechanisms is a potential solution but is becoming more difficult. Here we report an antibacterial mechanism that safeguards intestine cells from enteropathogenic Escherichia coli (EPEC) by shutting down an infection-responsive signal of the host intestine cell. A key step in EPEC infection of intestinal cells involves Tir-induced actin reorganization. Nck mediates this event by binding with Tir through its SH2 domain (Nck-SH2) and with WIP through its second SH3 domain (Nck-SH3.2). Here we report the design of a synthetic peptide that reacts precisely with a unique cysteine of the Nck-SH3.2 domain, blocks the binding site of the Nck protein, and prevents EPEC infection of Caco-2 cells. Oral update of this nontoxic peptide before EPEC administration safeguards mice from EPEC infection and diarrhea. This study demonstrates domain-specific blockage of an SH3 domain of a multidomain adaptor protein inside cells and the inhibition of Tir-induced rearrangement of the host actin cytoskeleton as a previously unknown antibacterial mechanism.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/antagonistas & inibidores , Peptídeos Catiônicos Antimicrobianos/farmacologia , Escherichia coli Enteropatogênica/efeitos dos fármacos , Infecções por Escherichia coli/prevenção & controle , Proteínas de Escherichia coli/antagonistas & inibidores , Interações Hospedeiro-Patógeno/efeitos dos fármacos , Proteínas Oncogênicas/antagonistas & inibidores , Receptores de Superfície Celular/antagonistas & inibidores , Actinas/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/química , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Peptídeos Catiônicos Antimicrobianos/uso terapêutico , Células CACO-2 , Escherichia coli Enteropatogênica/metabolismo , Proteínas de Escherichia coli/química , Proteínas de Escherichia coli/metabolismo , Humanos , Mucosa Intestinal/metabolismo , Mucosa Intestinal/microbiologia , Camundongos , Camundongos Endogâmicos C57BL , Proteínas Oncogênicas/química , Proteínas Oncogênicas/metabolismo , Ligação Proteica , Receptores de Superfície Celular/química , Receptores de Superfície Celular/metabolismo , Transdução de Sinais , Domínios de Homologia de src
16.
Sci Rep ; 10(1): 2743, 2020 02 17.
Artigo em Inglês | MEDLINE | ID: mdl-32066809

RESUMO

trans-Fatty acids (TFAs) are unsaturated fatty acids that contain one or more carbon-carbon double bonds in trans configuration. Epidemiological evidence has linked TFA consumption with various disorders, including cardiovascular diseases. However, the underlying pathological mechanisms are largely unknown. Here, we show a novel toxic mechanism of TFAs triggered by DNA damage. We found that elaidic acid (EA) and linoelaidic acid, major TFAs produced during industrial food manufacturing (so-called as industrial TFAs), but not their corresponding cis isomers, facilitated apoptosis induced by doxorubicin. Consistently, EA enhanced UV-induced embryonic lethality in C. elegans worms. The pro-apoptotic action of EA was blocked by knocking down Sab, a c-Jun N-terminal kinase (JNK)-interacting protein localizing at mitochondrial outer membrane, which mediates mutual amplification of mitochondrial reactive oxygen species (ROS) generation and JNK activation. EA enhanced doxorubicin-induced mitochondrial ROS generation and JNK activation, both of which were suppressed by Sab knockdown and pharmacological inhibition of either mitochondrial ROS generation, JNK, or Src-homology 2 domain-containing protein tyrosine phosphatase 1 (SHP1) as a Sab-associated protein. These results demonstrate that in response to DNA damage, TFAs drive the mitochondrial JNK-Sab-ROS positive feedback loop and ultimately apoptosis, which may provide insight into the common pathogenetic mechanisms of diverse TFA-related disorders.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Fragmentação do DNA/efeitos dos fármacos , Ácido Linoleico/farmacologia , Mitocôndrias/efeitos dos fármacos , Ácidos Oleicos/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/antagonistas & inibidores , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Apoptose/efeitos dos fármacos , Apoptose/genética , Apoptose/efeitos da radiação , Caenorhabditis elegans , Proteínas de Caenorhabditis elegans/antagonistas & inibidores , Proteínas de Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/metabolismo , Linhagem Celular Tumoral , Fragmentação do DNA/efeitos da radiação , Doxorrubicina/farmacologia , Embrião não Mamífero , Retroalimentação Fisiológica , Regulação da Expressão Gênica , Fatores de Troca do Nucleotídeo Guanina/antagonistas & inibidores , Fatores de Troca do Nucleotídeo Guanina/genética , Fatores de Troca do Nucleotídeo Guanina/metabolismo , Células HEK293 , Células HeLa , Células Endoteliais da Veia Umbilical Humana/citologia , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Camundongos , Mitocôndrias/metabolismo , Osteoblastos/citologia , Osteoblastos/efeitos dos fármacos , Osteoblastos/metabolismo , Proteína Tirosina Fosfatase não Receptora Tipo 6/genética , Proteína Tirosina Fosfatase não Receptora Tipo 6/metabolismo , Células RAW 264.7 , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Espécies Reativas de Oxigênio/agonistas , Raios Ultravioleta
17.
J Biol Chem ; 295(10): 3269-3284, 2020 03 06.
Artigo em Inglês | MEDLINE | ID: mdl-32005669

RESUMO

Nuclear accumulation of the small phosphoprotein integrin cytoplasmic domain-associated protein-1 (ICAP1) results in recruitment of its binding partner, Krev/Rap1 interaction trapped-1 (KRIT1), to the nucleus. KRIT1 loss is the most common cause of cerebral cavernous malformation, a neurovascular dysplasia resulting in dilated, thin-walled vessels that tend to rupture, increasing the risk for hemorrhagic stroke. KRIT1's nuclear roles are unknown, but it is known to function as a scaffolding or adaptor protein at cell-cell junctions and in the cytosol, supporting normal blood vessel integrity and development. As ICAP1 controls KRIT1 subcellular localization, presumably influencing KRIT1 function, in this work, we investigated the signals that regulate ICAP1 and, hence, KRIT1 nuclear localization. ICAP1 contains a nuclear localization signal within an unstructured, N-terminal region that is rich in serine and threonine residues, several of which are reportedly phosphorylated. Using quantitative microscopy, we revealed that phosphorylation-mimicking substitutions at Ser-10, or to a lesser extent at Ser-25, within this N-terminal region inhibit ICAP1 nuclear accumulation. Conversely, phosphorylation-blocking substitutions at these sites enhanced ICAP1 nuclear accumulation. We further demonstrate that p21-activated kinase 4 (PAK4) can phosphorylate ICAP1 at Ser-10 both in vitro and in cultured cells and that active PAK4 inhibits ICAP1 nuclear accumulation in a Ser-10-dependent manner. Finally, we show that ICAP1 phosphorylation controls nuclear localization of the ICAP1-KRIT1 complex. We conclude that serine phosphorylation within the ICAP1 N-terminal region can prevent nuclear ICAP1 accumulation, providing a mechanism that regulates KRIT1 localization and signaling, potentially influencing vascular development.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Núcleo Celular/metabolismo , Serina/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/antagonistas & inibidores , Proteínas Adaptadoras de Transdução de Sinal/genética , Sequência de Aminoácidos , Animais , Células CHO , Domínio Catalítico , Cricetinae , Cricetulus , Humanos , Proteína KRIT1/metabolismo , Mutagênese Sítio-Dirigida , Fosforilação , Quinases Ativadas por p21/química , Quinases Ativadas por p21/metabolismo
18.
Oncogene ; 39(12): 2568-2582, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31988454

RESUMO

Circulating tumor cells (CTC) disseminating is an important cause of distant metastasis. However, the mechanism involved in increasing the numbers of CTCs in breast cancer is unclear. Herein, Zinc finger protein 367 (ZNF367) was identified as a potential prometastatic gene in an integrative breast cancer datasets. ZNF367 was upregulated in breast cancer tissues and cell lines, and significantly correlated with poorer metastasis-free and overall survivals in patients. ZNF367 promoted tumor metastasis accompanied with increase of CTC numbers. Mechanistically, ZNF367 interacted with chromatin remodeling protein BRG1 and transcriptionally activated CIT and TP53BP2, leading to the inhibition of the Hippo pathway and activation of YAP1, which gave rise to the resistance of anoikis and increased CTCs in the blood circulation. More importantly, administration of a YAP1 inhibitor Verteporfin resensitized ZNF367-overexpressing breast cancer cells to anoikis and abrogated metastasis. Our findings addressed the importance of ZNF367 in breast cancer as a prognostic biomarker and offered a potential therapeutic strategy for the treatment of a subset of metastatic breast cancer with ZNF367 overexpression.


Assuntos
Neoplasias da Mama/metabolismo , Fatores de Transcrição Kruppel-Like/metabolismo , Metástase Neoplásica , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/antagonistas & inibidores , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Anoikis , Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , DNA Helicases/metabolismo , Feminino , Humanos , Neoplasias Pulmonares/secundário , Sistema de Sinalização das MAP Quinases , Camundongos , Camundongos Endogâmicos BALB C , Proteínas Nucleares/metabolismo , Prognóstico , Taxa de Sobrevida , Fatores de Transcrição/antagonistas & inibidores , Fatores de Transcrição/metabolismo
19.
Am J Respir Cell Mol Biol ; 62(4): 479-492, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31944822

RESUMO

Idiopathic pulmonary fibrosis is a lung disease with limited therapeutic options that is characterized by pathological fibroblast activation and aberrant lung remodeling with scar formation. YAP (Yes-associated protein) is a transcriptional coactivator that mediates mechanical and biochemical signals controlling fibroblast activation. In this study, we developed a high-throughput small-molecule screen for YAP inhibitors in primary human lung fibroblasts. Multiple HMG-CoA (hydroxymethylglutaryl-coenzyme A) reductase inhibitors (statins) were found to inhibit YAP nuclear localization via induction of YAP phosphorylation, cytoplasmic retention, and degradation. We further show that the mevalonate pathway regulates YAP activation, and that simvastatin treatment reduces fibrosis markers in activated human lung fibroblasts and in the bleomycin mouse model of pulmonary fibrosis. Finally, we show that simvastatin modulates YAP in vivo in mouse lung fibroblasts. Our results highlight the potential of small-molecule screens for YAP inhibitors and provide a mechanism for the antifibrotic activity of statins in idiopathic pulmonary fibrosis.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/antagonistas & inibidores , Proteínas de Ciclo Celular/antagonistas & inibidores , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Fibrose Pulmonar/tratamento farmacológico , Acil Coenzima A/metabolismo , Animais , Biomarcadores/metabolismo , Bleomicina/farmacologia , Núcleo Celular/efeitos dos fármacos , Núcleo Celular/metabolismo , Citoplasma/efeitos dos fármacos , Citoplasma/metabolismo , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Humanos , Ácido Mevalônico/metabolismo , Camundongos , Fosfoproteínas/metabolismo , Fibrose Pulmonar/metabolismo , Transdução de Sinais/efeitos dos fármacos , Sinvastatina/farmacologia , Bibliotecas de Moléculas Pequenas/farmacologia
20.
PLoS Biol ; 18(1): e3000591, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31929526

RESUMO

A major challenge for cancer immunotherapy is sustaining T-cell activation and recruitment in immunosuppressive solid tumors. Here, we report that the levels of the Hippo pathway effector Yes-associated protein (Yap) are sharply induced upon the activation of cluster of differentiation 4 (CD4)-positive and cluster of differentiation 8 (CD8)-positive T cells and that Yap functions as an immunosuppressive factor and inhibitor of effector differentiation. Loss of Yap in T cells results in enhanced T-cell activation, differentiation, and function, which translates in vivo to an improved ability for T cells to infiltrate and repress tumors. Gene expression analyses of tumor-infiltrating T cells following Yap deletion implicates Yap as a mediator of global T-cell responses in the tumor microenvironment and as a negative regulator of T-cell tumor infiltration and patient survival in diverse human cancers. Collectively, our results indicate that Yap plays critical roles in T-cell biology and suggest that Yap inhibition improves T-cell responses in cancer.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/fisiologia , Proteínas de Ciclo Celular/fisiologia , Quimiotaxia de Leucócito/genética , Linfócitos T/fisiologia , Microambiente Tumoral/imunologia , Proteínas Adaptadoras de Transdução de Sinal/antagonistas & inibidores , Proteínas Adaptadoras de Transdução de Sinal/genética , Animais , Proteínas de Ciclo Celular/antagonistas & inibidores , Proteínas de Ciclo Celular/genética , Proliferação de Células/genética , Células Cultivadas , Regulação para Baixo/genética , Regulação para Baixo/imunologia , Imunoterapia Adotiva , Melanoma Experimental/imunologia , Melanoma Experimental/patologia , Melanoma Experimental/terapia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neoplasias Cutâneas/imunologia , Neoplasias Cutâneas/patologia , Neoplasias Cutâneas/terapia , Microambiente Tumoral/genética
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