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1.
Int J Mol Sci ; 24(13)2023 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-37445964

RESUMO

Clinacanthus nutans (Burm. f.) Lindau has been used as a traditional herbal medicine for treating snake bites, scalds, burns, and viral and bacterial infections. It has been attracting an increasing amount of attention because of its biological activities, including its antidiabetic, antioxidant, antibacterial, anticancer, anti-inflammatory, antiviral, and immunoregulatory activities. Here, we conducted a panoramic survey of the literature regarding the immunoregulatory, anti-inflammatory, and antiviral activities of C. nutans. We discovered that C. nutans extracts have virucidal activities against herpes simplex virus types 1 and 2, varicella-zoster virus, cyprinid herpesvirus 3, porcine reproductive and respiratory syndrome virus, mosquito-borne chikungunya virus, and potentially SARS-CoV-2; such activities likely result from C. nutans interfering with the entry, penetration, infection, and replication of viruses. We also reviewed the phytochemicals in C. nutans extracts that exhibit anti-inflammatory and immunoregulatory activities. This updated review of the antiviral, anti-inflammatory, and immunoregulatory activities of C. nutans may guide future agricultural practices and reveal clinical applications of C. nutans.


Assuntos
Acanthaceae , COVID-19 , Animais , Antivirais/farmacologia , Extratos Vegetais/farmacologia , SARS-CoV-2 , Anti-Inflamatórios/farmacologia
2.
Nanotechnology ; 26(10): 105101, 2015 Mar 13.
Artigo em Inglês | MEDLINE | ID: mdl-25693888

RESUMO

Benzo[a]pyrene (BaP), a component of cooking oil fumes (COF), promotes lung cancer cell proliferation and survival via the induction of inhibitor of apoptosis protein-2 (IAP-2) proteins. Thus knockdown of IAP-2 would be a promising way to battle against lung cancer caused by COF. Functionalized gold nanoparticle (AuNP) is an effective delivery system for bio-active materials. Here, biocompatible hyaluronic acid (HA) was fabricated into nanoparticles to increase the target specificity by binding to CD44-over-expressed cancer cells. IAP-2-specific small-interfering RNA (siRNAs) or fluorescein isothiocyanate (FITC) were then incorporated into AuNP-HA. Conjugation of IAP-2 siRNA into AuNPs-HA was verified by the UV-vis spectrometer and Fourier transform infrared spectrometer. Further studies showed that AuNP-HA/FITC were effectively taken up by A549 cells through CD44-mediated endocytosis. Incubation of BaP-challenged cells with AuNP-HA-IAP-2 siRNAs silenced the expression of IAP-2, decreased cell proliferation and triggered pronounced cell apoptosis by the decrease in Bcl-2 protein and the increase in Bax protein as well as the active form of caspases-3. The BaP-elicited cell migration and enzymatic activity of the secreted matrix metalloproteinase-2 were also substantially suppressed by treatment with AuNP-HA-IAP-2 siRNAs. These results indicated that IAP-2 siRNAs can be efficiently delivered into A549 cells by functionalized AuNP-HA to repress the IAP-2 expression and BaP-induced oncogenic events, suggesting the potential therapeutic application of IAP-2 siRNA or other siRNA-conjugated AuNP-HA composites to COF-induced lung cancer and other gene-caused diseases in the future.


Assuntos
Sistemas de Liberação de Medicamentos/instrumentação , Ouro/química , Ácido Hialurônico/química , Proteínas Inibidoras de Apoptose/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Nanopartículas/uso terapêutico , RNA Interferente Pequeno/uso terapêutico , Benzo(a)pireno/toxicidade , Materiais Biocompatíveis , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Humanos , Receptores de Hialuronatos , Proteínas Inibidoras de Apoptose/administração & dosagem , Neoplasias Pulmonares/induzido quimicamente , Nanopartículas/química , RNA Interferente Pequeno/administração & dosagem , Espécies Reativas de Oxigênio
3.
Artigo em Inglês | MEDLINE | ID: mdl-34135980

RESUMO

Clinacanthus nutans is a traditional medicinal herb that is applied for the therapy of snake bites, skin infection, herpes infection, burns, scalds, dysentery, and diabetes. Clinacanthus nutans is also used to treat several cancers, including breast, cervical, colon, gastric, head and neck, liver, lung, pancreatic, and skin cancers, as well as lymphoma and leukemia; however, the underlying mechanisms of its anticancer activity remained undetermined. We searched PubMed and Google with key words "Clinacanthus nutans and cancer" and collected recent papers of Clinacanthus nutans with anticancer activity. We focused on the preparation, effects, and action mechanisms of Clinacanthus nutans extracts on various types of cancers. We hope that this mini review can help update our knowledge about active components, effects, and molecular mechanisms of extracts from this promising herb Clinacanthus nutans for ongoing studies and speed up its clinical application in the future.

4.
Oncogene ; 38(26): 5113-5126, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30867567

RESUMO

Keratin intermediate filament (IF) is one component of cellular architectures, which provides necessary mechanical support to conquer environmental stresses. Recent findings reveal its involvement in mechano-transduction and the associated stem cell reprogramming, suggesting the possible roles in cancer development. Here, we report t(12;17)(q13.13;q21.2) chromosomal rearrangement as the most common fusion event in OSCC, resulting in a variety of inter-keratin fusions. Junction site mapping verified 9 in-frame K6-K14 variants, three of which were correlated with lymph node invasion, late tumor stages (T3/T4) and shorter disease-free survival times. When expressed in OSCC cells, those fusion variants disturbed wild-type K14 organization through direct interaction or aggregate formation, leading to perinuclear structure loss and nuclear deformation. Protein array analyses showed the ability of K6-K14 variant 7 (K6-K14/V7) to upregulate TGF-ß and G-CSF signaling, which contributed to cell stemness, drug tolerance, and cell aggressiveness. Notably, K6-K14/V7-expressing cells easily adapted to a soft 3-D culture condition in vitro and formed larger, less differentiated tumors in vivo. In addition to the anti-mechanical-stress activity, our data uncover oncogenic functionality of novel keratin filaments caused by gene fusions during OSCC development.


Assuntos
Carcinoma de Células Escamosas/patologia , Queratina-14/fisiologia , Queratina-6/fisiologia , Neoplasias Bucais/patologia , Células-Tronco Neoplásicas/fisiologia , Animais , Carcinogênese/genética , Carcinogênese/patologia , Carcinoma de Células Escamosas/genética , Desdiferenciação Celular/genética , Humanos , Queratina-14/genética , Queratina-6/genética , Masculino , Camundongos , Camundongos Nus , Neoplasias Bucais/genética , Células NIH 3T3 , Invasividade Neoplásica , Células-Tronco Neoplásicas/metabolismo , Proteínas Recombinantes de Fusão/genética , Células Tumorais Cultivadas
5.
Sci Rep ; 7(1): 8062, 2017 08 14.
Artigo em Inglês | MEDLINE | ID: mdl-28808311

RESUMO

Coenzyme Q0 (CoQ0, 2,3-dimethoxy-5-methyl-1,4-benzoquinone) has been reported to exert anticancer properties against human breast/lung cancer cells. This study investigated the in vitro and in vivo anticancer properties of CoQ0 on human ovarian carcinoma (SKOV-3) cells and xenografted nude mice, and revealed the underlying molecular mechanism. CoQ0 induced G2/M arrest through downregulation of cyclin B1/A and CDK1/K2 expressions. CoQ0-induced autophagy as a survival mechanism was evidenced by increased accumulation of LC3-II, GFP-LC3 puncta, AVOs formation and Beclin-1/Bcl-2 dysregulation. Increased TUNEL-positive cells and Annexin-V/PI stained cells indicated CoQ0-induced late apoptosis. Both mitochondrial (caspase-3, PARP and Bax/Bcl-2 dysregulation) and ER stress (caspase-12 and Hsp70) signals are involved in execution of apoptosis. Interestingly, CoQ0-induced apoptosis/autophagy is associated with suppression of HER-2/neu and PI3K/AKT signalling cascades. CoQ0 triggered intracellular ROS production, whereas antioxidant N-acetylcysteine prevented CoQ0-induced apoptosis, but not autophagy. Inhibition of apoptosis by Z-VAD-FMK suppressed CoQ0-induced autophagy (diminished LC3-II/AVOs), indicates CoQ0-induced apoptosis led to evoke autophagy. Contrary, inhibition of autophagy by 3-MA/CQ potentiated CoQ0-induced apoptosis (increased DNA fragmentation/PARP cleavage). Furthermore, CoQ0 treatment to SKOV-3 xenografted nude mice reduced tumor incidence and burden. Histopathological analyses confirmed that CoQ0 modulated xenografted tumor progression by apoptosis induction. Our findings emphasize that CoQ0 triggered ROS-mediated apoptosis and cytoprotective autophagy.


Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Coenzimas/farmacologia , Neoplasias Ovarianas/tratamento farmacológico , Substâncias Protetoras/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Animais , Proteína Beclina-1/metabolismo , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Feminino , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacos , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Neoplasias Ovarianas/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Receptor ErbB-2/metabolismo , Transdução de Sinais/efeitos dos fármacos
6.
Sci Rep ; 7(1): 372, 2017 03 23.
Artigo em Inglês | MEDLINE | ID: mdl-28337019

RESUMO

The bioflavonoid apigenin has been shown to possess cancer-preventive and anti-cancer activities. In a drug screening, we found that apigenin can inhibit Wnt/ß-catenin signaling, a pathway that participates in pivotal biological functions, which dis-regulation results in various human diseases including cancers. However, the underlying mechanism of apigenin in this pathway and its link to anti-cancer activities remain largely unknown. Here we showed that apigenin reduced the amount of total, cytoplasmic, and nuclear ß-catenin, leading to the suppression in the ß-catenin/TCF-mediated transcriptional activity, the expression of Wnt target genes, and cell proliferation of Wnt-stimulated P19 cells and Wnt-driven colorectal cancer cells. Western blotting and immunofluorescent staining analyses further revealed that apigenin could induce autophagy-mediated down-regulation of ß-catenin in treated cells. Treatment with autophagy inhibitors wortmannin and chloroquine compromised this effect, substantiating the involvement of autophagy-lysosomal system on the degradation of ß-catenin during Wnt signaling through inhibition of the AKT/mTOR signaling pathway. Our data not only pointed out a route for the inhibition of canonical Wnt signaling through the induction of autophagy-lysosomal degradation of key player ß-catenin, but also suggested that apigenin or other treatments which can initiate this degradation event are potentially used for the therapy of Wnt-related diseases including cancers.


Assuntos
Apigenina/administração & dosagem , Autofagia , Lisossomos/metabolismo , Via de Sinalização Wnt , beta Catenina/metabolismo , Linhagem Celular Tumoral , Proliferação de Células , Neoplasias Colorretais/metabolismo , Proteínas Desgrenhadas/metabolismo , Humanos , Proteína-5 Relacionada a Receptor de Lipoproteína de Baixa Densidade/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Serina-Treonina Quinases TOR/metabolismo
7.
Oncotarget ; 7(16): 22409-26, 2016 Apr 19.
Artigo em Inglês | MEDLINE | ID: mdl-26968952

RESUMO

Coenzyme Q0 (CoQ0, 2,3-dimethoxy-5-methyl-1,4-benzoquinone), a novel quinone derivative, has been shown to modulate cellular redox balance. However, effect of this compound on melanoma remains unclear. This study examined the in vitro or in vivo anti-tumor, apoptosis, and anti-metastasis activities of CoQ0 (0-20 µM) through inhibition of Wnt/ß-catenin signaling pathway. CoQ0 exhibits a significant cytotoxic effect on melanoma cell lines (B16F10, B16F1, and A2058), while causing little toxicity toward normal (HaCaT) cells. The suppression of ß-catenin was seen with CoQ0 administration accompanied by a decrease in the expression of Wnt/ß-catenin transcriptional target c-myc, cyclin D1, and survivin through GSK3ß-independent pathway. We found that CoQ0 treatment caused G1 cell-cycle arrest by reducing the levels of cyclin E and CDK4. Furthermore, CoQ0 treatment induced apoptosis through caspase-9/-3 activation, PARP degradation, Bcl-2/Bax dysregulation, and p53 expression. Notably, non- or sub-cytotoxic concentrations of CoQ0 markedly inhibited migration and invasion, accompanied by the down-regulation of MMP-2 and -9, and up-regulation of TIMP-1 and -2 expressions in highly metastatic B16F10 cells. Furthermore, the in vivo study results revealed that CoQ0 treatment inhibited the tumor growth in B16F10 xenografted nude mice. Histological analysis and western blotting confirmed that CoQ0 significantly decreased the xenografted tumor progression as demonstrated by induction of apoptosis, suppression of ß-catenin, and inhibition of cell cycle-, apoptotic-, and metastatic-regulatory proteins. The data suggest that CoQ0 unveils a novel mechanism by down-regulating Wnt/ß-catenin pathways and could be used as a potential lead compound for melanoma chemotherapy.


Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Benzoquinonas/farmacologia , Melanoma/patologia , Via de Sinalização Wnt/efeitos dos fármacos , Animais , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Humanos , Camundongos , Camundongos Nus , Invasividade Neoplásica/patologia , Ensaios Antitumorais Modelo de Xenoenxerto
8.
Int J Oncol ; 43(1): 141-50, 2013 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-23677180

RESUMO

Quinazolinone derivatives are known to possess anticancer activities on cell metastasis and cell death in different human cancer cell lines. Here, we studied the anti-metastasis activity and the underlying mechanisms of the novel quinazoline derivative MJ-56 (6-pyrrolidinyl-2-(3-bromostyryl)quinazolin-4-one). MJ-56 inhibited cell migration and invasion of HT29 human colorectal cancer cells by wound-healing and Matrigel-coated transwell assays in a concentration-dependent manner. MJ-56-treated cells resulted in the reduced expression of matrix metalloproteinase (MMP)-2, -7, -9 and -10 and the reduced enzymatic activities of MMP-2 and MMP-9. In contrast, MJ-56-treated cells enhanced the expression of the tissue inhibitors of metalloproteinases (TIMPs) TIMP-1 and TIMP-2. Further analyses showed that MJ-56 attenuated the activities of epidermal growth factor receptor (EGFR), c-Met and the downstream ERK-mediated MAPK and PI3K/AKT/mTOR signaling pathways, which led to decreased protein synthesis by dephosphorylating the translation initiation factors eIF-4B, eIF-4E, eIF-4G and S6 ribosomal protein. In addition, MJ-56 interfered with the NF-κB signaling via impairing PI3K/AKT activation and subsequently reduced the NF-κB-mediated transcription of MMPs. Taken together, the reduced expression of phosphor-EGFR and c-MET is chiefly responsible for all events of blocking metastasis. Our results suggest a potential role of MJ-56 on therapy of colorectal cancer metastasis.


Assuntos
Neoplasias Colorretais/patologia , Receptores ErbB/metabolismo , Proteínas Proto-Oncogênicas c-met/biossíntese , Quinazolinonas/administração & dosagem , Estirenos/administração & dosagem , Ativação Transcricional/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Neoplasias Colorretais/tratamento farmacológico , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/biossíntese , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Células HT29 , Humanos , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Invasividade Neoplásica/patologia , Proteínas Proto-Oncogênicas c-met/metabolismo , Quinazolinas/farmacologia , Transdução de Sinais , Inibidor Tecidual de Metaloproteinase-1 , Inibidor Tecidual de Metaloproteinase-2
9.
Int J Oncol ; 43(2): 629-37, 2013 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-23754208

RESUMO

Phenethyl isothiocyanate (PEITC) is a natural compound that is involved in chemoprevention as well as inhibition of cell growth and induction of apoptosis in several types of cancer cells. Previous studies have revealed that PEITC suppresses the invasion of AGS gastric and HT-29 colorectal cancer cells. However, the effects of PEITC on the metastasis of SAS oral cancer cells remain to be determined. Our results showed that PEITC treatment inhibited the invasion of EGF-stimulated SAS cells in a concentration-dependent manner, but appeared not to affect the cell viability. The expression and enzymatic activities of matrix metalloprotease-2 (MMP-2) and matrix metalloprotease-9 (MMP-9) were suppressed by PEITC. Concomitantly, we observed an increase in the protein expression of both tissue inhibitor of metalloproteinase-1 (TIMP-1) and -2 (TIMP-2) in treated cells. Furthermore, PEITC treatments decreased the protein phosphorylation of epidermal growth factor receptor (EGFR) and downstream signaling proteins including PDK1, PI3K (p85), AKT, phosphorylated IKK and IκB to inactivate NF-κB for the suppression of MMP-2 and MMP-9 expression. In addition, PEITC can trigger the MAPK signaling pathway through the increase in phosphorylated p38, JNK and ERK in treated cells. Our data indicate that PEITC is able to inhibit the invasion of EGF-stimulated SAS oral cancer cells by targeting EGFR and its downstream signaling molecules and finally lead to the reduced expression and enzymatic activities of both MMP-2 and MMP-9. These results suggest that PEITC is promising for the therapy of oral cancer metastasis.


Assuntos
Anticarcinógenos/farmacologia , Carcinoma de Células Escamosas/tratamento farmacológico , Receptores ErbB/metabolismo , Isotiocianatos/farmacologia , Neoplasias Bucais/tratamento farmacológico , Carcinoma de Células Escamosas/patologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Fator de Crescimento Epidérmico/metabolismo , Receptores ErbB/efeitos dos fármacos , Humanos , Quinase I-kappa B/metabolismo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Metaloproteinase 2 da Matriz/biossíntese , Metaloproteinase 2 da Matriz/efeitos dos fármacos , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/biossíntese , Metaloproteinase 9 da Matriz/efeitos dos fármacos , Metaloproteinase 9 da Matriz/metabolismo , Neoplasias Bucais/patologia , NF-kappa B/metabolismo , Invasividade Neoplásica , Fosfatidilinositol 3-Quinases/metabolismo , Fosforilação/efeitos dos fármacos , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Piruvato Desidrogenase Quinase de Transferência de Acetil , Transdução de Sinais/efeitos dos fármacos , Inibidor Tecidual de Metaloproteinase-1/biossíntese , Inibidor Tecidual de Metaloproteinase-2/biossíntese
10.
Oncol Rep ; 30(2): 925-32, 2013 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-23708932

RESUMO

Kaempferol is a natural flavonoid that possesses anti-proliferative and apoptosis-inducing activities in several cancer cell lines. In the present study, we investigated the anti-metastatic activity of kaempferol and its molecular mechanism(s) of action in human osteosarcoma cells. Kaempferol displayed inhibitory effects on the invasion and adhesion of U-2 osteosarcoma (OS) cells in a concentration-dependent manner by Matrigel Transwell assay and cell adhesion assay. Kaempferol also inhibited the migration of U-2 OS cells in a concentration-dependent manner at different treatment time points by wound-healing assay. Additional experiments showed that kaempferol treatment reduced the enzymatic activities and protein levels of matrix metalloproteinase (MMP)-2, MMP-9 and urokinase plasminogen activator (uPA) by gelatin and casein-plasminogen zymography assays and western blot analyses. Kaempferol also downregulated the mRNA levels of MMP-2 and MMP-9 by quantitative PCR analyses. Furthermore, kaempferol was able to reduce the protein phosphorylation of ERK, p38 and JNK by western blotting. By electrophoretic mobility-shift assay (EMSA), we demonstrated that kaempferol decreased the DNA binding activity of AP-1, an action likely to result in the reduced expression of MMP-2, MMP-9 and uPA. Collectively, our data showed that kaempferol attenuated the MAPK signaling pathways including ERK, JNK and p38 and resulted in the decreased DNA binding ability of AP-1, and hence, the downregulation in the expression and enzymatic activities of MMP-2, MMP-9 and uPA, contributing to the inhibition of metastasis of U-2 OS cells. Our results suggest a potential role of kaempferol in the therapy of tumor metastasis of OS.


Assuntos
Neoplasias Ósseas/tratamento farmacológico , Quempferóis/farmacologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Osteossarcoma/tratamento farmacológico , Transdução de Sinais/efeitos dos fármacos , Fator de Transcrição AP-1/metabolismo , Neoplasias Ósseas/genética , Neoplasias Ósseas/metabolismo , Neoplasias Ósseas/patologia , Adesão Celular/efeitos dos fármacos , Adesão Celular/genética , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Movimento Celular/genética , Regulação para Baixo/efeitos dos fármacos , Regulação para Baixo/genética , Humanos , Metaloproteinase 2 da Matriz/genética , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/genética , Metaloproteinase 9 da Matriz/metabolismo , Metástase Neoplásica , Osteossarcoma/genética , Osteossarcoma/metabolismo , Osteossarcoma/patologia , Fosforilação , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ativador de Plasminogênio Tipo Uroquinase/genética , Ativador de Plasminogênio Tipo Uroquinase/metabolismo
11.
Biochem Pharmacol ; 84(9): 1143-53, 2012 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-22935447

RESUMO

Wnts are secreted glycolipoproteins that play important roles in the regulation of embryonic development and tissue homeostasis. Binding of Wnt to receptors and co-receptors causes inactivation of the ß-catenin destruction complex, which leads to the stabilization and nuclear translocation of ß-catenin to initiate Wnt-responsive gene expression after associating with TCF in the nucleus. As its deregulation results in serious human diseases, especially cancers, the Wnt signaling pathway serves as a promising platform for screening anti-cancer drugs. Resveratrol was selected based on its ability to inhibit the ß-catenin/TCF-mediated transcriptional activity. Resveratrol, a natural phytoalexin found in a variety of plants, possesses health-promoting properties including anti-aging, anti-inflammatory, anti-oxidant, anti-cancer, cardioprotective and neuroprotective activities. We found that resveratrol indeed exhibited dose-dependent suppression of Wnt signaling, reduced the expression of Wnt target genes such as cyclin D1 and conductin, and inhibited the growth of Wnt-stimulated cells and Wnt-driven colorectal cancer cells. Further studies indicated that resveratrol functions downstream of GSK3ß. Treatment with resveratrol did not alter the amount of ß-catenin and its distribution in the cytoplasm and nucleus, suggesting that resveratrol did not affect the accumulation and nuclear targeting of ß-catenin. In contrast, co-immunoprecipitation and in vitro binding analyses substantiated that resveratrol was capable of disrupting the binding between ß-catenin and TCF4, contributing to the decreased Wnt signaling. Our discoveries not only reveal a novel target of resveratrol in the Wnt signaling pathway but also show the potential of therapy with harmless resveratrol in colorectal cancer and other Wnt-related diseases.


Assuntos
Antineoplásicos/farmacologia , Estilbenos/farmacologia , Fatores de Transcrição TCF/metabolismo , Proteínas Wnt/metabolismo , beta Catenina/metabolismo , Transporte Ativo do Núcleo Celular , Animais , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/metabolismo , Linhagem Celular , Linhagem Celular Tumoral , Núcleo Celular/metabolismo , Proliferação de Células , Sobrevivência Celular/efeitos dos fármacos , Neoplasias do Colo , Quinase 3 da Glicogênio Sintase/genética , Glicogênio Sintase Quinase 3 beta , Humanos , Ligação Proteica , Resveratrol , Transdução de Sinais , Fator de Transcrição 4 , Fatores de Transcrição/metabolismo , Transcrição Gênica
12.
Biochem Pharmacol ; 79(3): 389-98, 2010 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-19765549

RESUMO

ITR-284, a potent anti-leukemia agent of carboxamide derivative, has been shown to inhibit the proliferation of leukemia cells. In this study, the underlying molecular mechanisms in vitro and anti-leukemia activity in vivo of ITR-284 were investigated. ITR-284 reduced the cell viability and induced apoptosis in HL-60 and WEHI-3 leukemia cells. Following exposure of cells to 30 nM of ITR-284, there is a time-dependent decrease in the mitochondrial membrane potential (DeltaPsi(m)) and an increase in the reactive oxygen species (ROS). ITR-284 treatment also caused a time-dependent increase of Fas/CD95, cytosolic cytochrome c, cytosolic active form of caspase-8/-9/-3, cytosolic Apaf-1 and Bax, and the decrease of Bcl-2. However, the ITR-284-induced caspase-8/-9 and -3 activities can be blocked by pan-caspase inhibitor (Z-VAD-FMK). In addition, the anti-leukemia effects of ITR-284 in vivo were further evaluated in BALB/c mice inoculated with WEHI-3 cells. Orally treatment with ITR-284 (2 and 10mg/kg/alternate day for 7 times) increased the survival rate and prevented the loss of body weight in leukemia mice. The enlargement of spleen and infiltration of immature myeloblastic cells into spleen red pulp were significantly reduced in ITR-284-treated mice compared with control mice. Moreover, ITR-284 application can enhance the anti-leukemia effect of all-trans retinoic acid (ATRA). These results revealed that ITR-284 acted against both HL-60 and WEHI-3 in vitrovia both intrinsic and extrinsic apoptotic signaling pathways, and exhibited an anti-leukemic effect in a WEHI-3 orthotopic mice model of leukemia.


Assuntos
Antineoplásicos/uso terapêutico , Inibidores do Crescimento/uso terapêutico , Leucemia Experimental/tratamento farmacológico , Tiofenos/uso terapêutico , Amidas/química , Amidas/uso terapêutico , Animais , Antineoplásicos/química , Linhagem Celular Tumoral , Inibidores do Crescimento/química , Células HL-60 , Humanos , Leucemia Experimental/metabolismo , Leucemia Experimental/patologia , Camundongos , Camundongos Endogâmicos BALB C , Tiofenos/química , Tiofenos/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto/métodos
13.
Genes Dev ; 20(14): 1933-45, 2006 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-16815997

RESUMO

MACF1 (microtubule actin cross-linking factor 1) is a multidomain protein that can associate with microfilaments and microtubules. We found that MACF1 was highly expressed in neuronal tissues and the foregut of embryonic day 8.5 (E8.5) embryos and the head fold and primitive streak of E7.5 embryos. MACF1(-/-) mice died at the gastrulation stage and displayed developmental retardation at E7.5 with defects in the formation of the primitive streak, node, and mesoderm. This phenotype was similar to Wnt-3(-/-) and LRP5/6 double-knockout embryos. In the absence of Wnt, MACF1 associated with a complex that contained Axin, beta-catenin, GSK3beta, and APC. Upon Wnt stimulation, MACF1 appeared to be involved in the translocation and subsequent binding of the Axin complex to LRP6 at the cell membrane. Reduction of MACF1 with small interfering RNA decreased the amount of beta-catenin in the nucleus, and led to an inhibition of Wnt-induced TCF/beta-catenin-dependent transcriptional activation. Similar results were obtained with a dominant-negative MACF1 construct that contained the Axin-binding region. Reduction of MACF1 in Wnt-1-expressing P19 cells resulted in decreased T (Brachyury) gene expression, a DNA-binding transcription factor that is a direct target of Wnt/beta-catenin signaling and required for mesoderm formation. These results suggest a new role of MACF1 in the Wnt signaling pathway.


Assuntos
Proteínas dos Microfilamentos/metabolismo , Transdução de Sinais , Proteínas Wnt/metabolismo , Proteína da Polipose Adenomatosa do Colo/metabolismo , Animais , Proteína Axina , Sequência de Bases , Proteínas de Transporte/genética , Proteínas de Transporte/metabolismo , Membrana Celular/metabolismo , Proteínas do Citoesqueleto/genética , Proteínas do Citoesqueleto/metabolismo , Distonina , Regulação da Expressão Gênica no Desenvolvimento , Quinase 3 da Glicogênio Sintase/metabolismo , Glicogênio Sintase Quinase 3 beta , Mesoderma/patologia , Camundongos , Camundongos Knockout , Proteínas dos Microfilamentos/genética , Dados de Sequência Molecular , Complexos Multiproteicos , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Estrutura Terciária de Proteína , Transporte Proteico , Proteínas Repressoras/metabolismo , Proteínas Wnt/genética , beta Catenina/metabolismo
14.
J Cell Sci ; 118(Pt 16): 3727-38, 2005 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-16076900

RESUMO

MACF1 (microtubule actin crosslinking factor), also called ACF7 (actin crosslinking family 7) is a cytoskeletal linker protein that can associate with both actin filaments and microtubules. We have identified a novel alternatively spliced isoform of MACF1. We named this isoform MACF1b and renamed the original isoform MACF1a. MACF1b is identical to MACF1a, except that it has a region containing plakin (or plectin) repeats in the middle of the molecule. MACF1b is ubiquitously expressed in adult tissues with especially high levels in the lung. We studied the subcellular localization of MACF1b proteins in mammalian cell lines. In two lung cell lines, MACF1b was chiefly localized to the Golgi complex. Upon treatments that disrupt the Golgi complex, MACF1b redistributed into the cytosol, but remained co-localized with the dispersed Golgi ministacks. MACF1b proteins can be detected in the enriched Golgi fraction by western blotting. The domain of MACF1b that targets it to the Golgi was found at the N-terminal part of the region that contains the plakin repeats. Reducing the level of MACF1 proteins by small-interfering RNA resulted in the dispersal of the Golgi complex.


Assuntos
Complexo de Golgi/metabolismo , Membranas Intracelulares/metabolismo , Proteínas dos Microfilamentos/metabolismo , Plaquinas/metabolismo , Animais , Células COS , Compartimento Celular/fisiologia , Chlorocebus aethiops , Regulação para Baixo/fisiologia , Células Epiteliais/metabolismo , Células Epiteliais/ultraestrutura , Regulação da Expressão Gênica/fisiologia , Humanos , Membranas Intracelulares/ultraestrutura , Pulmão/metabolismo , Pulmão/ultraestrutura , Proteínas dos Microfilamentos/genética , Dados de Sequência Molecular , Plaquinas/genética , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Estrutura Terciária de Proteína/fisiologia , RNA Interferente Pequeno
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