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1.
J Pharm Sci ; 108(9): 3106-3111, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-30991038

RESUMO

Rifampin (RIF) has been widely used for the treatment of bacterial infections, including tuberculosis (TB). Treatment of drug-resistant TB is a global problem because of reduced drug efficacy. The present study determined the effect of RIF on MDR1 gene (P-glycoprotein, P-gp) expression in THP1 macrophages and analyzed the intracellular concentration of the anti-TB drug prothionamide in the presence of RIF. RIF treatment significantly induced MDR1 protein and mRNA levels in phorbol 12-myristate 13-acetate-stimulated THP1 macrophages (p < 0.001 and 0.01, respectively). The pregnane X receptor inhibitors resveratrol and ketoconazole significantly suppressed RIF-induced P-gp expression in THP1 macrophages (p < 0.05). RIF-treated THP1 macrophages also exhibited strong efflux of P-gp substrate, resulting in a reduced intracellular concentration of rhodamine-123 and prothionamide (p < 0.01 and 0.05, respectively). By contrast, the P-gp inhibitor cyclosporine A significantly increased intracellular concentration of rhodamine-123 and prothionamide (p < 0.001 and 0.05, respectively). The present results suggest that the usage of RIF together with P-gp-substrate drugs to treat TB may lead to deteriorated treatment efficacy because of the lower intracellular drug concentration. Further studies would be necessary to know the influence of RIF-induced P-gp induction on the treatment outcome of patients with TB.


Assuntos
Antituberculosos/farmacologia , Macrófagos/metabolismo , Protionamida/farmacocinética , Rifampina/farmacologia , Subfamília B de Transportador de Cassetes de Ligação de ATP/metabolismo , Antituberculosos/uso terapêutico , Linhagem Celular Tumoral , Antagonismo de Drogas , Farmacorresistência Bacteriana/efeitos dos fármacos , Quimioterapia Combinada/efeitos adversos , Humanos , Líquido Intracelular/metabolismo , Protionamida/uso terapêutico , Rifampina/uso terapêutico , Tuberculose/tratamento farmacológico , Tuberculose/microbiologia , Regulação para Cima/efeitos dos fármacos
2.
Artigo em Inglês | MEDLINE | ID: mdl-30533717

RESUMO

We have identified the whole-genome sequence of Lactobacillus salivarius DJ-sa-01, a potential probiotic strain for poultry, isolated from a chicken small intestine. We used the PacBio and Illumina platforms to obtain the sequence of the entire single circular chromosome.

3.
Artigo em Inglês | MEDLINE | ID: mdl-30533732

RESUMO

We report here the complete genome sequence of Lactobacillus johnsonii strain Byun-jo-01, which was isolated from the murine gastrointestinal tract. The genome was determined using both PacBio and Illumina sequencing. L. johnsonii strain Byun-jo-01 contains a single circular chromosome of 1,959,519 bp, and its GC content is 34.7%.

4.
Artigo em Inglês | MEDLINE | ID: mdl-30533759

RESUMO

Lactic acid bacteria (LAB) are generally recognized as safe (GRAS) and serve as probiotic bacteria when consumed in adequate amounts. Here, we report the complete genome sequence of Lactobacillus reuteri Byun-re-01, isolated from mouse small intestine.

5.
Artigo em Inglês | MEDLINE | ID: mdl-30533821

RESUMO

Lactobacillus reuteri SKKU-OGDONS-01 is a potentially indigenous probiotic strain isolated from the small intestine of a 27-week-old chicken. The complete genome of L. reuteri SKKU-OGDONS-01 comprises a single circular chromosome. Its length is 2,259,968 bp, with a G+C content of 38.9%.

6.
J Pharmacol Sci ; 138(4): 279-283, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30424926

RESUMO

The aim of this study was to assess the effects of Keishibukuryogan (K-06) and Shakuyakukanzoto (TJ-68), commercial herbal medicines, on the substrate uptake activities of renal organic anion transporters. We performed transporter uptake and cell viability assays in Xenopus oocytes and HEK293 human kidney embryonic cells treated with K-06 or TJ-68. K-06 and TJ-68 markedly inhibited the substrate uptake activities of URAT1, OAT1, and OAT3, while they did not exhibit non-cytotoxic effects. Our findings demonstrated that K-06 and TJ-68 inhibited the substrate uptake activities of renal transporters, suggesting their mechanism of action as nephroprotective agents.


Assuntos
Medicamentos de Ervas Chinesas/farmacologia , Transportadores de Ânions Orgânicos/metabolismo , Animais , Transporte Biológico , Combinação de Medicamentos , Glycyrrhiza , Células HEK293 , Humanos , Medicina Kampo , Oócitos , Transportadores de Ânions Orgânicos/genética , Paeonia , Xenopus
7.
Genes (Basel) ; 9(6)2018 May 29.
Artigo em Inglês | MEDLINE | ID: mdl-29844265

RESUMO

Probiotics are well known for their beneficial effects for animals, including humans and livestock. Here, we tested the probiotic activity of Lactobacillus paracasei expressing 3D8 scFv, a nucleic acid-hydrolyzing mini-antibody, in mice intestine. A total of 18 fecal samples derived from three different conditions at two different time points were subjected to high-throughput 16S ribosomal RNA (rRNA) metagenomic analyses. Bioinformatic analyses identified an average of 290 operational taxonomic units. After administration of L. paracasei, populations of the probiotics L. paracasei, Lactobacillus reuteri, and Pediococcus acidilactici increased, whereas the population of harmful bacteria such as Helicobacter species decreased. Furthermore, continuous administration of L. paracasei resulted in L. paracasei emerging as the dominant probiotic after competition with other existing probiotics. Expression of 3D8 scFv protein specifically increased the population of P. acidilactici, which is another probiotic. In summary, our results showed that L. paracasei expressing 3D8 scFv protein enhanced probiotic activity in mice intestine with no observable side effects. Thus, the system developed in this study may be a good tool for the expression of recombinant protein using probiotics.

8.
Sci Rep ; 7(1): 35, 2017 02 24.
Artigo em Inglês | MEDLINE | ID: mdl-28232732

RESUMO

Although surgery and radiation are beneficial for treating cancer, they can also lead to malfunctions of the lymphatic system such as secondary lymphedema. This abnormality of the lymphatic system is characterized by severe swelling, adipogenesis, inflammation, and fibrosis in the lymphedematous region. Moreover, the proliferation of fibrotic tissue in the lymphedematous region generates edema that is no longer spontaneously reversible. No treatment for fibrosis has been validated in patients with lymphedema. In our efforts to develop a therapeutic agent for lymphedema fibrosis, we used a newly established mouse hind limb model. Previous studies have demonstrated that hyaluronic acid accumulates in the lymphedematous region. Thus, we challenged mice with of hyaluronidase (HYAL), with the aim of reducing fibrogenesis. After subcutaneous injections in the lymphedematous mouse leg every two days, the volume of lymphedema had reduced significantly by 7 days post-operation. Histochemical analysis indicated that collagen accumulation and myofibroblast differentiation were decreased in epidermal tissues after HYAL injection. Moreover, it was associated with upregulation of interferon-gamma, increased numbers of Th1 cells, and downregulation of interleukin-4 and interleukin-6 in the lymphedematous region and spleen. These results indicate that hydrolysis of hyaluronic acid can boost an anti-fibrotic immune response in the mouse lymphedema model.


Assuntos
Fibrose/tratamento farmacológico , Ácido Hialurônico/metabolismo , Hialuronoglucosaminidase/uso terapêutico , Linfedema/tratamento farmacológico , Células Th1/metabolismo , Animais , Colágeno/metabolismo , Fibrose/imunologia , Interferon gama/metabolismo , Interleucina-4/metabolismo , Interleucina-6/metabolismo , Extremidade Inferior , Linfedema/imunologia , Masculino , Camundongos , Miofibroblastos/metabolismo , Baço/metabolismo , Células Th1/imunologia
9.
Cell Signal ; 31: 124-134, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-28077325

RESUMO

In this study, we presented the role of 14-3-3σ to activate CK2-Hsp90ß-PXR-MDR1 pathway on rifampin and paclitaxel treated LS174T cells and in vivo LS174T cell-xenografted nude mouse model. Following several in vitro and in vivo experiments, rifampin and paclitaxel were found to be stimulated the CK2-Hsp90ß-PXR-MDR1 pathway. Of the proteins in this pathway, Pregnane X receptor (PXR) is a representative transcription factor of multidrug resistance protein 1 (MDR1). We constructed FLAG-PXR-LS174T stable cell lines and discovered 22 proteins that interacted with PXR on rifampin treatment. Among them, Hsp90ß and 14-3-3σ were isolated for further study. Both the proteins were found to be localized in cytoplasm on rifampin treatment by using confocal microscopy. On the other hand, PXR was found to be localized in nucleus after rifampin and paclitaxel treatment by using cell fractionation assay. In Western blot analysis, rifampin did not influence the expression of 14-3-3σ protein. Transient transfection of 14-3-3σ into LS174T cells induced overexpression of PXR; however, P-glycoprotein (P-gp) was not changed significantly. P-gp overexpression was induced only when 14-3-3σ transfected LS174T cells were treated with rifampin and paclitaxel, whereas 14-3-3σ inhibition by nonpeptidic inhibitor, BV02 and 14-3-3σ siRNA reduced rifampin induced PXR and P-gp expression. Cell survival rates were much higher at 14-3-3σ-LS174T stable cell lines than LS174T cells following paclitaxel and vincristine treatment. This data indicates that 14-3-3σ contributes to P-gp overexpression through interaction with PXR with rifampin and paclitaxel treatment.


Assuntos
Proteínas 14-3-3/metabolismo , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Biomarcadores Tumorais/metabolismo , Exorribonucleases/metabolismo , Paclitaxel/farmacologia , Receptores de Esteroides/metabolismo , Rifampina/farmacologia , Sequência de Aminoácidos , Animais , Antineoplásicos/farmacologia , Sítios de Ligação , Sobrevivência Celular/efeitos dos fármacos , Cromatografia Líquida , Feminino , Proteínas de Choque Térmico HSP90/metabolismo , Humanos , Camundongos Nus , Modelos Biológicos , Receptor de Pregnano X , Ligação Proteica/efeitos dos fármacos , Receptores de Esteroides/química , Espectrometria de Massas em Tandem
10.
Viruses ; 7(9): 5133-44, 2015 Sep 21.
Artigo em Inglês | MEDLINE | ID: mdl-26402693

RESUMO

The antiviral effect of a catalytic RNA-hydrolyzing antibody, 3D8 scFv, for intranasal administration against avian influenza virus (H1N1) was described. The recombinant 3D8 scFv protein prevented BALB/c mice against H1N1 influenza virus infection by degradation of the viral RNA genome through its intrinsic RNA-hydrolyzing activity. Intranasal administration of 3D8 scFv (50 µg/day) for five days prior to infection demonstrated an antiviral activity (70% survival) against H1N1 infection. The antiviral ability of 3D8 scFv to penetrate into epithelial cells from bronchial cavity via the respiratory mucosal layer was confirmed by immunohistochemistry, qRT-PCR, and histopathological examination. The antiviral activity of 3D8 scFv against H1N1 virus infection was not due to host immune cytokines or chemokines, but rather to direct antiviral RNA-hydrolyzing activity of 3D8 scFv against the viral RNA genome. Taken together, our results suggest that the RNase activity of 3D8 scFv, coupled with its ability to penetrate epithelial cells through the respiratory mucosal layer, directly prevents H1N1 virus infection in a mouse model system.


Assuntos
Anticorpos Catalíticos/administração & dosagem , Antivirais/administração & dosagem , Células Epiteliais/imunologia , Vírus da Influenza A Subtipo H1N1/imunologia , Infecções por Orthomyxoviridae/prevenção & controle , Ribonucleases/administração & dosagem , Anticorpos de Cadeia Única/administração & dosagem , Administração Intranasal , Animais , Antivirais/farmacocinética , Hidrólise , Camundongos Endogâmicos BALB C , RNA Viral/metabolismo , Anticorpos de Cadeia Única/farmacocinética , Resultado do Tratamento
11.
J Biol Chem ; 290(27): 17029-40, 2015 Jul 03.
Artigo em Inglês | MEDLINE | ID: mdl-25995454

RESUMO

The P-glycoprotein (P-gp) encoded by the MDR1 gene is a drug-exporting transporter located in the cellular membrane. P-gp induction is regarded as one of the main mechanisms underlying drug-induced resistance. Although there is great interest in the regulation of P-gp expression, little is known about its underlying regulatory mechanisms. In this study, we demonstrate that casein kinase 2 (CK2)-mediated phosphorylation of heat shock protein 90ß (Hsp90ß) and subsequent stabilization of PXR is a key mechanism in the regulation of MDR1 expression. Furthermore, we show that CK2 is directly activated by rifampin. Upon exposure to rifampin, CK2 catalyzes the phosphorylation of Hsp90ß at the Ser-225/254 residues. Phosphorylated Hsp90ß then interacts with PXR, causing a subsequent increase in its stability, leading to the induction of P-gp expression. In addition, inhibition of CK2 and Hsp90ß enhances the down-regulation of PXR and P-gp expression. The results of this study may facilitate the development of new strategies to prevent multidrug resistance and provide a plausible mechanism for acquired drug resistance by CK2-mediated regulation of P-gp expression.


Assuntos
Proteínas de Choque Térmico HSP90/metabolismo , Rifampina/farmacologia , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Subfamília B de Transportador de Cassetes de Ligação de ATP/metabolismo , Motivos de Aminoácidos , Caseína Quinase II/química , Caseína Quinase II/genética , Caseína Quinase II/metabolismo , Linhagem Celular Tumoral , Regulação da Expressão Gênica/efeitos dos fármacos , Proteínas de Choque Térmico HSP90/química , Proteínas de Choque Térmico HSP90/genética , Humanos , Simulação de Acoplamento Molecular , Fosforilação/efeitos dos fármacos , Receptor de Pregnano X , Receptores de Esteroides/genética , Receptores de Esteroides/metabolismo , Rifampina/química
12.
Mol Pharmacol ; 79(6): 1014-22, 2011 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-21406604

RESUMO

Galangin is a naturally occurring bioflavonoid with anticancer activity against certain human cancers, yet little is known about its mechanism of action. Here, we used a chemical biology approach to reveal that galangin suppresses ß-catenin response transcription (CRT), which is aberrantly up-regulated in colorectal and liver cancers, by promoting the degradation of intracellular ß-catenin. Inhibition of glycogen synthase kinase-3ß (GSK-3ß) activity or mutation of the GSK-3ß-targeted sequence from ß-catenin was unable to abrogate the galangin-mediated degradation of ß-catenin. In addition, galangin down-regulated the intracellular ß-catenin levels in cancer cells with inactivating mutations of adenomatous polyposis coli (APC) or Axin, which are components of the ß-catenin destruction complex. Galangin repressed the expression of ß-catenin/T-cell factor-dependent genes, such as cyclin D1 and c-myc, and thus inhibited the proliferation of CRT-positive cancer cells. Structure-activity data indicated that the major structural requirements for galangin-mediated ß-catenin degradation are hydroxyl groups at positions 3, 5, and 7. Our findings suggest that galangin exerts its anticancer activity by promoting APC/Axin/GSK-3ß-independent proteasomal degradation of ß-catenin.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Proteína da Polipose Adenomatosa do Colo/metabolismo , Proliferação de Células/efeitos dos fármacos , Flavonoides/farmacologia , Quinase 3 da Glicogênio Sintase/metabolismo , Proteínas Repressoras/metabolismo , Transcrição Gênica , beta Catenina/metabolismo , Proteína Axina , Linhagem Celular , Regulação para Baixo/efeitos dos fármacos , Glicogênio Sintase Quinase 3 beta , Humanos , Hidrólise
13.
Biochem Biophys Res Commun ; 391(1): 915-20, 2010 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-19962966

RESUMO

Molecular lesions in Wnt/beta-catenin signaling and subsequent up-regulation of beta-catenin response transcription (CRT) occur frequently during the development of colon cancer. To identify small molecules that suppress CRT, we screened natural compounds in a cell-based assay for detection of TOPFalsh reporter activity. Murrayafoline A, a carbazole alkaloid isolated from Glycosmis stenocarpa, antagonized CRT that was stimulated by Wnt3a-conditioned medium (Wnt3a-CM) or LiCl, an inhibitor of glycogen synthase kinase-3beta (GSK-3beta), and promoted the degradation of intracellular beta-catenin without altering its N-terminal phosphorylation at the Ser33/37 residues, marking it for proteasomal degradation, or the expression of Siah-1, an E3 ubiquitin ligase. Murrayafoline A repressed the expression of cyclin D1 and c-myc, which is known beta-catenin/T cell factor (TCF)-dependent genes and thus inhibited the proliferation of various colon cancer cells. These findings indicate that murrayafoline A may be a potential chemotherapeutic agent for use in the treatment of colon cancer.


Assuntos
Alcaloides/farmacologia , Antineoplásicos/farmacologia , Carbazóis/farmacologia , Proliferação de Células/efeitos dos fármacos , Neoplasias do Colo/metabolismo , Proteínas Wnt/antagonistas & inibidores , beta Catenina/antagonistas & inibidores , Linhagem Celular Tumoral , Humanos , Proteínas Nucleares/metabolismo , Fosforilação/efeitos dos fármacos , Ubiquitina-Proteína Ligases/metabolismo , Proteínas Wnt/metabolismo , beta Catenina/metabolismo
14.
Biochem Biophys Res Commun ; 390(3): 500-5, 2009 Dec 18.
Artigo em Inglês | MEDLINE | ID: mdl-19800318

RESUMO

Wnt/beta-catenin signaling plays important roles in many developmental processes, including neural crest-derived melanocyte development. Here we show that cardamonin, a calchone from Aplinia katsumadai Hayata, inhibited pigmentation in melanocytes through suppression of Wnt/beta-catenin signaling pathway. Cardamonin significantly suppressed the expression of microphthalmia-associated transcription factor (MITF) and tyrosinase, which are melanocyte differentiation-associated markers, in human normal melanocytes, thereby decreasing intracellular melanin production. In addition, cardamonin promoted the degradation of intracellular beta-catenin that was accumulated by Wnt3a-conditioned medium (Wnt3a CM) or bromoindirubin-3'-oxime (BIO), a glycogen synthase kinase-3beta (GSK-3beta) inhibitor, in HEK293 reporter cells and human normal melanocytes. Our findings indicate that cardamonin may be a potential whitening agent for use in cosmetics and in the medical treatment of hyperpigmentation disorders.


Assuntos
Chalconas/farmacologia , Melaninas/antagonistas & inibidores , Melanócitos/efeitos dos fármacos , Pigmentação da Pele/efeitos dos fármacos , Proteínas Wnt/antagonistas & inibidores , beta Catenina/antagonistas & inibidores , Linhagem Celular , Quinase 3 da Glicogênio Sintase/antagonistas & inibidores , Humanos , Indóis/farmacologia , Melanócitos/metabolismo , Melanócitos/fisiologia , Oximas/farmacologia
15.
Biochem Biophys Res Commun ; 377(4): 1304-8, 2008 Dec 26.
Artigo em Inglês | MEDLINE | ID: mdl-19000900

RESUMO

Curcumin, a component of turmeric (Curcuma longa), has been reported to suppress beta-catenin response transcription (CRT), which is aberrantly activated in colorectal cancer. However, the effects of its natural analogs (demethoxycurcumin [DMC] and bisdemethoxycurcumin [BDMC]) and metabolite (tetrahydrocurcumin [THC]) on the Wnt/beta-catenin pathway have not been investigated. Here, we show that DMC and BDMC suppressed CRT that was activated by Wnt3a conditioned-medium (Wnt3a-CM) without altering the level of intracellular beta-catenin, and inhibited the growth of various colon cancer cells, with comparable potency to curcumin. Additionally, DMC and BDMC down-regulated p300, which is a positive regulator of the Wnt/beta-catenin pathway. Notably, THC also inhibited CRT and cell proliferation, but to a much lesser degree than curcumin, DMC, or BDMC, indicating that the conjugated bonds in the central seven-carbon chain of curcuminoids are essential for the inhibition of Wnt/beta-catenin pathway and the anti-proliferative activity of curcuminoids. Thus, our findings suggest that curcumin derivatives inhibit the Wnt/beta-catenin pathway by decreasing the amount of the transcriptional coactivator p300.


Assuntos
Antineoplásicos/farmacologia , Curcumina/análogos & derivados , Proteínas Wnt/antagonistas & inibidores , beta Catenina/antagonistas & inibidores , Fatores de Transcrição de p300-CBP/antagonistas & inibidores , Antineoplásicos/química , Linhagem Celular , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Neoplasias do Colo/metabolismo , Curcumina/química , Curcumina/farmacologia , Diarileptanoides , Regulação para Baixo , Humanos , Proteínas Wnt/genética , beta Catenina/genética , Fatores de Transcrição de p300-CBP/metabolismo
16.
Biochem Biophys Res Commun ; 367(1): 195-200, 2008 Feb 29.
Artigo em Inglês | MEDLINE | ID: mdl-18174026

RESUMO

The Wnt/beta-catenin signaling pathway plays important roles in cell differentiation. Activation of this pathway, likely by Wnt-10b, has been shown to inhibit adipogenesis in cultured 3T3-L1 preadipocytes and mice. Here we revealed that bisindoylmaleimide I (BIM), which is widely used as a specific inhibitor of protein kinase C (PKC), inhibits adipocyte differentiation through activation of the Wnt/beta-catenin signaling pathway. BIM increased beta-catenin responsive transcription (CRT) and up-regulated intracellular beta-catenin levels in HEK293 cells and 3T3-L1 preadipocytes. BIM significantly decreased intracellular lipid accumulation and reduced expression of important adipocyte marker genes including peroxisome-proliferator-activated receptor gamma (PPARgamma) and CAATT enhancer-binding protein alpha (C/EBPalpha) in 3T3-L1 preadipocytes. Taken together, our findings indicate that BIM inhibits adipogenesis by increasing the stability of beta-catenin protein in 3T3-L1 preadipocyte cells.


Assuntos
Adipócitos/efeitos dos fármacos , Adipogenia/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Indóis/farmacologia , Maleimidas/farmacologia , Proteína Quinase C/antagonistas & inibidores , beta Catenina/metabolismo , Células 3T3-L1 , Adipócitos/metabolismo , Adipócitos/patologia , Adipogenia/genética , Adipogenia/fisiologia , Animais , Sequência de Bases , Proteínas Estimuladoras de Ligação a CCAAT/metabolismo , Diferenciação Celular/fisiologia , Células Cultivadas , Camundongos , PPAR gama/metabolismo , Proteínas Wnt/genética , Proteínas Wnt/metabolismo , beta Catenina/genética
17.
Mol Pharmacol ; 72(6): 1599-606, 2007 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-17855653

RESUMO

Alterations in the Wnt/beta-catenin pathway are associated with the development and progression of human prostate cancer. Decursin, a pyranocoumarin isolated from the Korean Angelica gigas root, inhibits the growth of androgen-independent human prostate cancer cells, but little is known about its mechanism of action. Using a cell-based screen, we found that decursin attenuates the Wnt/beta-catenin pathway. Decursin antagonized beta-catenin response transcription (CRT), which was induced with Wnt3a-conditioned medium and LiCl, by promoting the degradation of beta-catenin. Furthermore, decursin suppressed the expression of cyclin D1 and c-myc, which are downstream target genes of beta-catenin and thus inhibited the growth of PC3 prostate cancer cells. In contrast, decursinol, in which the (CH3)2-C=CH-COO- side chain of decursin is replaced with -OH, had no effect on CRT, the level of intracellular beta-catenin, or PC3 cell proliferation. Our findings suggest that decursin exerts its anticancer activity in prostate cancer cells via inhibition of the Wnt/beta-catenin pathway.


Assuntos
Antagonistas de Androgênios/farmacologia , Androgênios/fisiologia , Benzopiranos/farmacologia , Butiratos/farmacologia , Proliferação de Células , Neoplasias da Próstata/prevenção & controle , beta Catenina/metabolismo , Antagonistas de Androgênios/metabolismo , Angelica , Benzopiranos/química , Butiratos/química , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Humanos , Masculino , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Raízes de Plantas , Neoplasias da Próstata/patologia , beta Catenina/antagonistas & inibidores
18.
J Cell Sci ; 119(Pt 22): 4702-9, 2006 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-17093267

RESUMO

Normally, the Wnt/beta-catenin pathway controls developmental processes and homeostasis, but abnormal activation of this pathway is a frequent event during the development of cancer. The key mechanism in regulation of the Wnt/beta-catenin pathway is the amino-terminal phosphorylation of beta-catenin, marking it for proteasomal degradation. Here we present small-molecule-based identification of protein kinase C (PKC)-mediated beta-catenin phosphorylation as a novel mechanism regulating the Wnt/beta-catenin pathway. We used a cell-based chemical screen to identify A23187, which inhibits the Wnt/beta-catenin pathway. PKC was activated by A23187 treatment and subsequently phosphorylated N-terminal serine (Ser) residues of beta-catenin, which promoted beta-catenin degradation. Moreover, the depletion of PKCalpha inhibited the phosphorylation and degradation of beta-catenin. Therefore, our findings suggest that the PKC pathway negatively regulates the beta-catenin level outside of the Wnt/beta-catenin pathway.


Assuntos
Complexo de Endopeptidases do Proteassoma/metabolismo , Proteína Quinase C-alfa/metabolismo , Proteínas Wnt/metabolismo , beta Catenina/metabolismo , Animais , Calcimicina/farmacologia , Cálcio/metabolismo , Linhagem Celular , Membrana Celular/metabolismo , Quinase 3 da Glicogênio Sintase/metabolismo , Glicogênio Sintase Quinase 3 beta , Humanos , Ionóforos/farmacologia , Camundongos , Fosforilação , Transporte Proteico , Transdução de Sinais
19.
Mol Pharmacol ; 70(3): 960-6, 2006 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-16735606

RESUMO

Aberrant activation of Wnt/beta-catenin signaling and subsequent up-regulation of beta-catenin response transcription (CRT) is a critical event in the development of human colon cancer. Thus, Wnt/beta-catenin signaling is an attractive target for the development of anticancer therapeutics. In this study, we identified hexachlorophene as an inhibitor of Wnt/beta-catenin signaling from cell-based small-molecule screening. Hexachlorophene antagonized CRT that was stimulated by Wnt3a-conditioned medium by promoting the degradation of beta-catenin. This degradation pathway is Siah-1 and adenomatous polyposis colidependent, but glycogen synthase kinase-3beta and F-box beta-transducin repeat-containing protein-independent. In addition, hexachlorophene represses the expression of cyclin D1, which is a known beta-catenin target gene, and inhibits the growth of colon cancer cells. Our findings suggest that hexachlorophene attenuates Wnt/beta-catenin signaling through the Siah-1-mediated beta-catenin degradation.


Assuntos
Anti-Infecciosos Locais/farmacologia , Hexaclorofeno/farmacologia , Proteínas Nucleares/metabolismo , Processamento de Proteína Pós-Traducional/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Ubiquitina-Proteína Ligases/metabolismo , Proteínas Wnt/metabolismo , beta Catenina/metabolismo , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Neoplasias do Colo/patologia , Regulação para Baixo/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Quinase 3 da Glicogênio Sintase/metabolismo , Glicogênio Sintase Quinase 3 beta , Hexaclorofeno/química , Humanos , Proteínas Nucleares/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Ubiquitina-Proteína Ligases/genética , Proteína Wnt3 , Proteína Wnt3A , beta Catenina/genética , Proteínas Contendo Repetições de beta-Transducina/metabolismo
20.
FEBS Lett ; 579(20): 4213-8, 2005 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-16051228

RESUMO

The dysregulation of Wnt/beta-catenin signaling and subsequent upregulation of beta-catenin response transcription (CRT) occur frequently in colon cancer cells. Non-steroidal anti-inflammatory drugs (NSAIDs) can repress CRT in colorectal cancer, but little is known about the mechanism of action. We show that the NSAID diclofenac inhibits Wnt/beta-catenin signaling without altering the level of beta-catenin protein and reduces the expression of beta-catenin/TCF-dependent genes. Diclofenac induced the degradation of IkappaBalpha, which increased free nuclear factor kappaB (NF-kappaB) in cells. Also, the ectopic expression of p65, which is a component of NF-kappaB, suppressed CRT. Our findings suggest that diclofenac inhibits Wnt/beta-catenin signaling via the activation of NF-kappaB in colon cancer cells.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Antineoplásicos/farmacologia , Neoplasias do Colo/metabolismo , Proteínas do Citoesqueleto/antagonistas & inibidores , Diclofenaco/farmacologia , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , NF-kappa B/metabolismo , Transativadores/antagonistas & inibidores , Proteínas de Ligação ao Cálcio/metabolismo , Neoplasias do Colo/genética , Proteínas do Citoesqueleto/metabolismo , Regulação para Baixo , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Glicoproteínas de Membrana/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Sinaptotagmina I , Sinaptotagminas , Transativadores/metabolismo , Transcrição Gênica/efeitos dos fármacos , Células Tumorais Cultivadas , Proteínas Wnt , beta Catenina
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