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1.
Ann N Y Acad Sci ; 1462(1): 65-78, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31495936

RESUMO

Oral squamous cell carcinoma (OSCC) is one of the most common cancer types, with a high annual incidence. Although chemotherapy contributes to suppressing OSCC tumorigenesis, the available treatments result in poor prognosis because of local recurrence and regional lymph node metastasis. Thus, it is necessary to discover novel and safe drugs with greater effectiveness and fewer side effects. Fucoidan is a component of the cell wall of brown seaweed that has been shown to produce a wide range of biological activities. The present study aimed to investigate the effectiveness of fucoidan in treating OSCC. In in vitro studies, we found that fucoidan inhibited OSCC growth and suppressed migration and invasion of OSCC cells. In addition, the potential interaction between fucoidan and filamin A (FLNA)-derived circular RNA (circFLNA) was predicted using bioinformatics databases and then confirmed in OSCC samples and cell lines. Indeed, fucoidan increased the expression of circFLNA in OSCC cell lines. Furthermore, both fucoidan and circFLNA could mediate the expression of key proteins related to cell growth, apoptosis, migration, and invasion. In conclusion, our research demonstrated that fucoidan might be considered as a potential natural drug in the treatment of OSCC patients by targeting circFLNA.


Assuntos
Antineoplásicos/farmacologia , Carcinoma de Células Escamosas/metabolismo , Filaminas/biossíntese , Neoplasias Bucais/metabolismo , Polissacarídeos/farmacologia , RNA Circular/biossíntese , Adulto , Idoso , Antineoplásicos/isolamento & purificação , Antineoplásicos/uso terapêutico , Carcinoma de Células Escamosas/tratamento farmacológico , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/fisiologia , Relação Dose-Resposta a Droga , Feminino , Filaminas/agonistas , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias Bucais/tratamento farmacológico , Extratos Vegetais/isolamento & purificação , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico , Polissacarídeos/isolamento & purificação , Polissacarídeos/uso terapêutico , RNA Circular/agonistas , Adulto Jovem
2.
Proc Natl Acad Sci U S A ; 115(39): 9744-9749, 2018 09 25.
Artigo em Inglês | MEDLINE | ID: mdl-30201720

RESUMO

Cotranslational folding (CTF) is a fundamental molecular process that ensures efficient protein biosynthesis and minimizes the formation of misfolded states. However, the complexity of this process makes it extremely challenging to obtain structural characterizations of CTF pathways. Here, we correlate observations of translationally arrested nascent chains with those of a systematic C-terminal truncation strategy. We create a detailed description of chain length-dependent free energy landscapes associated with folding of the FLN5 filamin domain, in isolation and on the ribosome, and thus, quantify a substantial destabilization of the native structure on the ribosome. We identify and characterize two folding intermediates formed in isolation, including a partially folded intermediate associated with the isomerization of a conserved cis proline residue. The slow folding associated with this process raises the prospect that neighboring unfolded domains might accumulate and misfold during biosynthesis. We develop a simple model to quantify the risk of misfolding in this situation and show that catalysis of folding by peptidyl-prolyl isomerases is sufficient to eliminate this hazard.


Assuntos
Filaminas/biossíntese , Humanos , Cinética , Espectroscopia de Ressonância Magnética , Modelos Moleculares , Dobramento de Proteína , Modificação Traducional de Proteínas , Deficiências na Proteostase/metabolismo , Ribossomos/metabolismo , Sequências de Repetição em Tandem , Termodinâmica
3.
Int J Biochem Cell Biol ; 103: 14-24, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30063986

RESUMO

Helicobacter pylori is the strongest known risk-factor for gastric cancer. However, its role in gastric cancer metastasis remains unclear. Previously we have reported that H. pylori promotes gastric cancer invasiveness by stabilizing the E3 ubiquitin ligase Siah2 which is mediated by Siah2 acetylation at Lys 139 (K139) residue. Here we identify that cell adhesion-related proteins testin (TES) and filamin-C (FLN-C) interact with Siah2 and get proteasomally degraded. The efficiency of TES and FLN-C degradation is significantly potentiated by K139-acetylated Siah2 (ac-K139 Siah2) in infected gastric cancer cells (GCCs). ac-Siah2-mediated downregulation of TES and FLN-C disrupts filopodia structures but promotes lamellipodia formation and enhances invasiveness and migration of infected GCCs. Since H. felis-infected mice as well as human gastric cancer biopsy samples also show high level of ac-K139 Siah2 and downregulated TES and FLN-C, we believe that acetylation of Siah2 is an important checkpoint that can be useful for therapeutic intervention.


Assuntos
Proteínas do Citoesqueleto/biossíntese , Regulação para Baixo , Filaminas/biossíntese , Regulação Neoplásica da Expressão Gênica , Infecções por Helicobacter/metabolismo , Helicobacter pylori/metabolismo , Proteínas com Domínio LIM/biossíntese , Proteínas de Neoplasias/metabolismo , Proteínas Nucleares/metabolismo , Neoplasias Gástricas , Ubiquitina-Proteína Ligases/metabolismo , Acetilação , Animais , Linhagem Celular Tumoral , Humanos , Camundongos , Invasividade Neoplásica , Proteínas de Ligação a RNA , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/microbiologia , Neoplasias Gástricas/patologia
4.
Hum Mol Genet ; 26(7): 1294-1304, 2017 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-28175289

RESUMO

Filamins are a family of actin-binding proteins responsible for diverse biological functions in the context of regulating actin dynamics and vesicle trafficking. Disruption of these proteins has been implicated in multiple human developmental disorders. To investigate the roles of different filamin isoforms, we focused on FlnA and FlnB interactions in the cartilage growth plate, since mutations in both molecules cause chondrodysplasias. Current studies show that FlnA and FlnB share a common function in stabilizing the actin cytoskeleton, they physically interact in the cytoplasm of chondrocytes, and loss of FlnA enhances FlnB expression of chondrocytes in the growth plate (and vice versa), suggesting compensation. Prolonged FlnB loss, however, promotes actin-stress fiber formation following plating onto an integrin activating substrate whereas FlnA inhibition leads to decreased actin formation. FlnA more strongly binds RhoA, although both filamins overlap with RhoA expression in the cell cytoplasm. FlnA promotes RhoA activation whereas FlnB indirectly inhibits this pathway. Moreover, FlnA loss leads to diminished expression of ß1-integrin, whereas FlnB loss promotes integrin expression. Finally, fibronectin mediated integrin activation has been shown to activate RhoA and activated RhoA leads to stress fiber formation and cell spreading. Fibronectin stimulation in null FlnA cells impairs enhanced spreading whereas FlnB inhibited cells show enhanced spreading. While filamins serve a primary static function in stabilization of the actin cytoskeleton, these studies are the first to demonstrate a dynamic and antagonistic relationship between different filamin isoforms in the dynamic regulation of integrin expression, RhoGTPase activity and actin stress fiber remodeling.


Assuntos
Filaminas/genética , Fibras de Estresse/genética , Proteína rhoA de Ligação ao GTP/genética , Citoesqueleto de Actina/genética , Citoesqueleto de Actina/metabolismo , Condrócitos/metabolismo , Fibronectinas/metabolismo , Filaminas/biossíntese , Regulação da Expressão Gênica no Desenvolvimento , Lâmina de Crescimento/metabolismo , Humanos , Integrina beta1/genética , Integrina beta1/metabolismo , Ligação Proteica , Fibras de Estresse/metabolismo , Proteína rhoA de Ligação ao GTP/metabolismo
5.
Neoplasma ; 63(2): 274-81, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26774150

RESUMO

An actin-binding protein filamin A connects the actin filament network to cell membrane receptors, and acts as a scaffold for various signaling pathways related to cancer growth and progression. Recently, it has been reported that filamin A is required for efficient regulation of early stages of DNA repair process. Moreover, some in vitro studies showed that the overexpression of filamin A determines resistance to various cytotoxic drugs, including cisplatin. We aimed to analyse the expression of filamin A protein in resected NSCLC (Non Small Cell Lung Cancer) specimens, to investigate the association of the level of filamin A protein expression and other clinicopathological features, and possible relationship between the expression of filamin A and survival outcome in NSCLC patients, treated with platinum-based combination chemotherapy. We performed filamin A protein immunohistochemistry on formalin-fixed and paraffin-embedded (FFPE) tissue sections from 135 NSCLC patients, using EP2405Y antibody against C-terminus of filamin A. Cytoplasmic, membranous and nuclear positivity of filamin A was evaluated semi-quantitatively and correlated with available clinicopathological data. Patients were divided into two groups for survival analysis (I group - patients treated with adjuvant platinum-based chemotherapy, II group - patients with surgical treatment only). We found significant positive correlation between filamin A protein expression and NSCLC stage (r=0.249; p<0,05), presence of lymph node (N)(r=0.205; p<0,05) and distant metastases (M) (r=0.332; P<0.01). Increased filamin A protein expression was significantly related with poor survival outcomes in patients with adjuvant platinum-based chemotherapy: OS (HR=1.005, 95%CI[1.000;1.010], p=0.037), DFS (HR=1.004, 95%CI [1.001:1.008], p=0,017). Multivariate Cox proportional hazards regression analysis also showed that overexpression of filamin A represents an independent risk factor for disease relapse, in addition to tumor size, stage, and metastases status (HR=1.723, 95%CI [1.021:2.909], p<0.05). Thus, filamin A expression might be a new prognostic marker in patients with NSCLC.


Assuntos
Antineoplásicos/uso terapêutico , Biomarcadores Tumorais/biossíntese , Carcinoma Pulmonar de Células não Pequenas/patologia , Cisplatino/uso terapêutico , Filaminas/biossíntese , Neoplasias Pulmonares/patologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Tumorais/genética , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Intervalo Livre de Doença , Feminino , Filaminas/genética , Humanos , Imuno-Histoquímica , Neoplasias Pulmonares/mortalidade , Metástase Linfática/patologia , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/genética , Resultado do Tratamento
6.
Tumour Biol ; 37(4): 5107-15, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26546439

RESUMO

A previous RNA interference (RNAi) screen identified filamin A (FLNA) as a potential biomarker to predict chemosensitivity in triple-negative breast cancer (TNBC). However, its ability to modulate chemosensitivity and the underlying mechanism has not been investigated. Genetic manipulation of FLNA expression has been performed in an immortalized noncancerous human mammary epithelial cell line and four TNBC cell lines to investigate its effect on chemosensitivity. Western blot analysis was performed to identify the potential signaling pathway involved. Xenograft mouse model was used to examine the in vivo role of FLNA in modulating chemosensitivity. Overexpression of FLNA conferred chemoresistance to docetaxel in noncancerous human mammary epithelial cells. Knockdown of FLNA sensitized four TNBC cell lines, MDA-MB-231, HCC38, Htb126, and HCC1937 to docetaxel which was reversed by reconstituted FLNA expression. Decreased FLNA expression correlated with decreased activation of ERK. Constitutive activation of ERK2 reversed siFLNA-induced chemosensitization. Inhibition of MEK1 recapitulates the effect of FLNA knockdown. MDA-MB-231 xenograft with FLNA knockdown showed enhanced response to docetaxel compared with control xenograft with increased apoptosis. FLNA can function as a modulator of chemosensitivity to docetaxel in TNBC cells through regulation of the MAPK/ERK pathway both in vitro and in vivo. FLNA may serve as a novel therapeutic target for improvement of chemotherapy efficacy in TNBC.


Assuntos
Biomarcadores Tumorais/genética , Resistencia a Medicamentos Antineoplásicos/genética , Filaminas/genética , Taxoides/administração & dosagem , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Animais , Apoptose/efeitos dos fármacos , Biomarcadores Tumorais/biossíntese , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Docetaxel , Feminino , Filaminas/biossíntese , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Técnicas de Silenciamento de Genes , Humanos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Glândulas Mamárias Humanas/citologia , Glândulas Mamárias Humanas/metabolismo , Camundongos , Interferência de RNA , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/patologia , Ensaios Antitumorais Modelo de Xenoenxerto
7.
Neuron ; 84(1): 78-91, 2014 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-25277454

RESUMO

Abnormal dendritic complexity is a shared feature of many neurodevelopmental disorders associated with neurological defects. Here, we found that the actin-crosslinking protein filamin A (FLNA) is overexpressed in tuberous sclerosis complex (TSC) mice, a PI3K-mTOR model of neurodevelopmental disease that is associated with abnormal dendritic complexity. Both under- and overexpression of FLNA in wild-type neurons led to more complex dendritic arbors in vivo, suggesting that an optimal level of FLNA expression is required for normal dendritogenesis. In Tsc1(null) neurons, knocking down FLNA in vivo prevented dendritic abnormalities. Surprisingly, FLNA overexpression in Tsc1(null) neurons was dependent on MEK1/2 but not mTOR activity, despite both pathways being hyperactive. In addition, increasing MEK-ERK1/2 activity led to dendritic abnormalities via FLNA, and decreasing MEK-ERK1/2 signaling in Tsc1(null) neurons rescued dendritic defects. These data demonstrate that altered FLNA expression increases dendritic complexity and contributes to pathologic dendritic patterning in TSC in an mTOR-independent, ERK1/2-dependent manner.


Assuntos
Dendritos/metabolismo , Filaminas/biossíntese , Regulação da Expressão Gênica , Sistema de Sinalização das MAP Quinases/fisiologia , Serina-Treonina Quinases TOR/metabolismo , Esclerose Tuberosa/metabolismo , Adulto , Animais , Animais Recém-Nascidos , Linhagem Celular Tumoral , Dendritos/patologia , Feminino , Filaminas/genética , Humanos , Masculino , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Pessoa de Meia-Idade , Técnicas de Cultura de Órgãos , Esclerose Tuberosa/patologia , Adulto Jovem
8.
Tumour Biol ; 35(3): 2641-8, 2014 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-24241900

RESUMO

This study aimed to analyze the expression and clinical significance of filamin A (FLNA) in gastric carcinoma and the biological effect in its cell line by FLNA overexpression. Immunohistochemistry and western blot were used to analyze FLNA protein expression in 47 cases of gastric cancer and 47 cases of normal tissues to study the relationship between FLNA expression and clinical factors. FLNA lentiviral vector and empty vector were respectively transfected into gastric cancer SGC-7901 cell line. Reverse transcription-polymerase chain reaction (RT-PCR) and western blot were used to detect the mRNA level and protein of FLNA. 3-[4,5-Dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) assay and migration and invasion assays were also conducted to determine the influence of the upregulated expression of FLNA that might be found on SGC-7901 cell biological effect. Immunohistochemistry: The level of FLNA protein expression was found to be significantly lower in gastric cancer tissue than normal tissues (P < 0.05). Western blot: The relative amount of FLNA protein in gastric cancer tissue was found to be significantly lower than in normal tissues (P < 0.05). The level of FLNA protein expression was not correlated with gender, age, and tumor invasion (P > 0.05), but it was correlated with lymph node metastasis, clinic stage, and histological grade (P < 0.05). Loss of FLNA expression correlated significantly with poor overall survival time by Kaplan-Meier analysis (P < 0.05). The result of biological function showed that SGC-7901 cell transfected FLNA had a lower survival fraction, significant decrease in migration and invasion, and lower matrix metallopeptidase 9 (MMP-9) protein expression compared with SGC-7901 cell untransfected FLNA (P < 0.05). FLNA expression decreased in gastric cancer and correlated significantly with lymph node metastasis, clinic stage, histological grade, and poor overall survival, suggesting that FLNA may play important roles as a negative regulator to gastric cancer SGC-7901 cell by promoting degradation of MMP-9.


Assuntos
Adenocarcinoma/metabolismo , Biomarcadores Tumorais/análise , Movimento Celular , Filaminas/biossíntese , Neoplasias Gástricas/metabolismo , Adenocarcinoma/mortalidade , Adenocarcinoma/patologia , Adulto , Idoso , Western Blotting , Linhagem Celular Tumoral , Movimento Celular/genética , Feminino , Filaminas/genética , Humanos , Imuno-Histoquímica , Estimativa de Kaplan-Meier , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Invasividade Neoplásica/genética , Estadiamento de Neoplasias , Prognóstico , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Neoplasias Gástricas/mortalidade , Neoplasias Gástricas/patologia , Transfecção , Adulto Jovem
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