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1.
Biochem Biophys Res Commun ; 649: 1-9, 2023 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-36738577

RESUMO

Aggressive cancers, such as triple-negative breast cancer (TNBC), are mostly fatal because of their potential to metastasize to distant organs. Cancer cells acquire various abilities to metastasize, including resistance to anoikis, an apoptotic cell death induced by loss of anchorage to the extracellular matrix. Transcriptional coactivator with PDZ binding motif (TAZ) and Yes-associated protein (YAP), the downstream effectors of the Hippo pathway, regulate cell- and tissue-level architectures by responding to mechanical microenvironments of cells, including the cell-extracellular matrix interaction. The Hippo pathway is frequently disrupted in cancer cells, and TAZ and YAP are irrelevantly activated, potentially resulting in anchorage-independent survival/proliferation of cancer cells and metastatic progression. The study aims to investigate the roles of TAZ and YAP in anoikis resistance in basal-like (BL) TNBC cells, which comprise a major subtype (>70%) of TNBC. We found that TAZ and YAP had nonredundant roles in anchorage-independent cancer cell survival or anoikis resistance. Particularly, TAZ was indispensable for anoikis resistance in BL-TNBC cells but not for survival of non-transformed mammary epithelial cells (MECs). In contrast, YAP, a paralog of TAZ, was indispensable for survival of both non-transformed MECs and cancer cells. Therefore, TAZ might be a preferable therapeutic target against dissemination of aggressive cancer cells without killing normal cells. Interestingly, TAZ was abnormally stabilized in BL-TNBC cells under non-adherent conditions, which promoted anoikis resistance. Furthermore, OTUB1, a deubiquitinating enzyme, was responsible for the stabilization of TAZ in detached BL-TNBC cells. Importantly, simultaneous high expression of TAZ and OTUB1 was associated with poor prognosis in BC. Thus, OTUB1 has emerged as a potentially druggable target. Successful inhibition of OTUB1 enzymatic activity is expected to downregulate TAZ and eventually prevents metastasis of aggressive cancers, such as BL-TNBC.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal , Neoplasias de Mama Triplo Negativas , Humanos , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Anoikis/fisiologia , Neoplasias de Mama Triplo Negativas/patologia , Proteínas de Sinalização YAP , Enzimas Desubiquitinantes/metabolismo , Microambiente Tumoral
2.
Cancer Sci ; 114(1): 152-163, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36102493

RESUMO

Recent comprehensive analyses of mtDNA and orthogonal RNA-sequencing data revealed that in numerous human cancers, mtDNA copy numbers and mtRNA amounts are significantly reduced, followed by low respiratory gene expression. Under such conditions (called mt-Low), cells encounter severe cell proliferation defects; therefore, they must acquire countermeasures against this fatal disadvantage during malignant transformation. This study elucidated a countermeasure against the mt-Low condition-induced antiproliferative effects in hepatocellular carcinoma (HCC) cells. The mechanism relied on the architectural transcriptional regulator HMGA2, which was preferably expressed in HCC cells of the mt-Low type in vitro and in vivo. Detailed in vitro analyses suggest that HMGA2 regulates insulin-like growth factor binding protein 1 (IGFBP1) expression, leading to AKT activation, which then phosphorylates the cyclin-dependent kinase inhibitor (CKI), P27KIP1, and facilitates its ubiquitin-mediated degradation. Accordingly, intervention in the HMGA2 function by RNAi resulted in an increase in P27KIP1 levels and an induction of senescence-like cell proliferation inhibition in mt-Low-type HCC cells. Conclusively, the HMGA2/IGFBP1/AKT axis has emerged as a countermeasure against P27KIP1 CKI upregulation under mt-Low conditions, thereby circumventing cell proliferation inhibition and supporting the tumorigenic state. Notably, similar to in vitro cell lines, HMGA2 was likely to regulate IGFBP1 expression in HCC in vivo, thereby contributing to poor patient prognosis. Considering the significant number of cases under mt-Low or the threat of CKI upregulation cancer-wide, the axis is noteworthy as a vulnerability of cancer cells or target for tumor-agnostic therapy inducing irreversible cell proliferation inhibition via CKI upregulation in a large population with cancer.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/patologia , Inibidor de Quinase Dependente de Ciclina p27/genética , Inibidor de Quinase Dependente de Ciclina p27/metabolismo , RNA , Proteínas Proto-Oncogênicas c-akt/metabolismo , Neoplasias Hepáticas/patologia , DNA Mitocondrial , Proteína 1 de Ligação a Fator de Crescimento Semelhante à Insulina , Proliferação de Células/genética , Inibidores de Proteínas Quinases/farmacologia , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica
3.
Cancer Sci ; 112(8): 3205-3217, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34036687

RESUMO

Previously, we reported that non-apoptotic cell death was induced in non-malignant mammary epithelial cells (HMECs) upon loss of anchorage during 48 h incubation in suspension. In this study, we examined HMECs in suspension at an earlier time point and found that most of them lost attachment ability to substrata when replated, although >80% were alive. This suggested that HMECs lost reattachment ability (RA) prior to cell death upon detachment. Concomitant with the loss of RA, a decrease in the levels of ß1 and ß4 integrin was observed. In sharp contrast, breast cancer cells retained integrin levels, reattached to substrata, and formed colonies after exposure to anchorage loss as efficiently as those maintained under adherent conditions. Such RA of cancer cells is essential for the metastatic process, especially for establishing adhesion contact with ECM in the secondary organ after systemic circulation. Further analysis suggested that sustained levels of ß4 integrin, which was mediated by Rac1, was critical for RA after anchorage loss and lung metastasis of breast cancer cells. In the cancer cells, persistent Rac1 activity enhanced escape of ß4 integrin from lysosomal degradation depending on actin-related protein 2/3 and TBC1D2, a GTPase-activating protein of Rab7 GTPase. Notably, simultaneous high expression of ITGB4 and RAC1 was associated with poor prognosis in patients with breast cancer. Therefore, ß4 integrin and Rac1 are attractive therapeutic targets to eliminate RA in cancer cells, thereby preventing the initial step of colonization at the secondary organ during metastasis.


Assuntos
Neoplasias da Mama/metabolismo , Integrina beta4/metabolismo , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/secundário , Proteínas rac1 de Ligação ao GTP/metabolismo , Adesão Celular , Linhagem Celular Tumoral , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Lisossomos/metabolismo , Células MCF-7 , Prognóstico
4.
Pharmacol Rep ; 73(3): 847-857, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33864630

RESUMO

BACKGROUND: Silver is a transition metal that is known to be less toxic than platinum. However, only few studies have reported the anticancer effects of some silver complexes and their possibility as an alternative to platinum complex. This study investigated the anticancer effects of the silver thiosulfate complex (STS), [Ag(S2O3)2]3-, consisting of silver and sodium thiosulfate. METHODS: In vitro cytotoxic activity of STS was investigated comparatively in human cancer cell lines (K562 and MCF-7) and normal human cells (mesenchymal stem cells and mammary epithelial cells). For its anticancer effects, cell cycle, mode of cell death, morphological changes, and accumulation of intracellular ROS and GSH were evaluated in MCF-7 to provide mechanistic insights. RESULTS: STS showed a concentration-dependent cytotoxicity in MCF-7 cell, which was abolished by pretreatment with N-acetylcysteine, suggesting ROS accumulation by STS. Moreover, STS caused cell cycle arrest at the G1 phase, decrease in the GSH levels, and morphological changes in MCF-7. Direct measurement of ROS demonstrated the elevation of intracellular ROS accumulation in cancer cells treated with STS; however, neither cytotoxicity nor ROS accumulation was observed in normal human cells. CONCLUSION: The results obtained here are the first evidence to show that STS exhibited an anticancer activity through ROS-induced mechanisms, and that its cytotoxicity is highly selective to cancer cells. The results of the present study warrant further investigation on the detailed mechanism of STS actions, as well as its in vivo effectiveness and safety for clinical application.


Assuntos
Antineoplásicos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Morte Celular/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Prata/farmacologia , Tiossulfatos/farmacologia , Apoptose/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Feminino , Fase G1/efeitos dos fármacos , Humanos , Células K562 , Células MCF-7
5.
ACS Omega ; 5(36): 23164-23174, 2020 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-32954167

RESUMO

Silibinin (Sib), one of the main components of milk thistle extract, has attracted considerable attention because of its various biological activities, which include antioxidant activity and potential effects in diabetes and Alzheimer's disease (AD). In a previous study, we synthesized catechin analogues by constraining the geometries of (+)-catechin and (-)-epicatechin. The constrained analogues exhibited enhanced bioactivities, with the only major difference between the two being their three-dimensional structures. The constrained geometry in (+)-catechin resulted in a high degree of planarity (PCat), while (-)-epicatechin failed to maintain planarity (PEC). The three-dimensional structure of Sib may be related to its ability to inhibit aggregation of amyloid beta (Aß). We therefore introduced PCat and PEC into Sib to demonstrate how the constrained molecular geometry and differences in three-dimensional structures may enhance such activities. Introduction of PCat into Sib (SibC) resulted in effective inhibition of Aß aggregation, α-glucosidase activity, and cell growth, suggesting that not only reduced flexibility but also the high degree of planarity may enhance the biological activity. SibC is expected to be a promising lead compound for the treatment of several diseases.

6.
Endocr J ; 67(8): 869-876, 2020 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-32350192

RESUMO

Radioactive iodine (RAI) therapy has been the mainstay of treatment for papillary thyroid carcinoma (PTC) patients with distant metastasis (DM). Although tyrosine kinase inhibitors (TKIs) were introduced for the treatment of RAI refractory metastatic thyroid carcinoma several years ago, clinical outcomes for PTC patients with DM treated using RAI therapy remain unclear. We retrospectively examined 64 PTC patients (9 men, 55 women) with DM at diagnosis treated using RAI therapy without administration of any kind of chemotherapy or TKIs. Median age of patients was 58 years. Site of DM was the lungs (n = 59), bone (n = 3), and pleural dissemination (n = 2). No patients showed multiple-organ metastases at diagnosis. By the end of the study period, 21 patients had died of PTC. Cause-specific survival rates at 10, 15, and 20 years after initial surgery were 68.2%, 63.6% and 61.1%, respectively. Uni- and multivariate analyses identified age ≥55 years (HR 3.1, p = 0.023), site of DM other than the lungs (HR 13.4, p < 0.0001), and DM with no RAI avidity (HR 5.1, p = 0.0098) as factors independently associated with disease-related death. When analyses were restricted to patients with lung metastasis (n = 59), surgical non-curability was another independent risk factor (HR 5.2, p = 0.0047) in addition to age and RAI avidity. According to risk stratification analysis based on these risk factors, patients with site of DM other than the lungs or with lung metastasis showing ≥2 risk factors among age ≥55 years, DM with no RAI avidity, and surgical non-curability are expected to show higher mortality rates.


Assuntos
Câncer Papilífero da Tireoide/diagnóstico , Câncer Papilífero da Tireoide/terapia , Neoplasias da Glândula Tireoide/diagnóstico , Neoplasias da Glândula Tireoide/terapia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Criança , Feminino , Humanos , Radioisótopos do Iodo/uso terapêutico , Japão/epidemiologia , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Prognóstico , Inibidores de Proteínas Quinases/uso terapêutico , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , Câncer Papilífero da Tireoide/epidemiologia , Câncer Papilífero da Tireoide/patologia , Neoplasias da Glândula Tireoide/epidemiologia , Neoplasias da Glândula Tireoide/patologia , Tireoidectomia/estatística & dados numéricos , Resultado do Tratamento , Adulto Jovem
7.
Exp Cell Res ; 389(1): 111889, 2020 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-32032602

RESUMO

The copy number of mitochondrial DNA (mtDNA) is decreased in most cancer types, including hepatocellular carcinoma (HCC), compared to normal counterparts. However, a decrease in mtDNA usually leads to defects in cell proliferation, which contradicts the robustness of cancer cell proliferation. In this study, we found that four out of seven HCC cell lines were of the mtDNA-less type. Interestingly, FOXM1, a member of the FOX transcription factor family, was highly expressed in a subset of them with proliferative potential maintained. B-MYB, a partner of FOXM1, was also expressed in the same cell lines. RNAi-mediated experiments demonstrated that when FOXM1/B-MYB was silenced in the cell lines, cell cycle-related genes were downregulated, while p21Cip1 was induced with senescence-associated ß-galactosidase, resulting in G1/S cell cycle arrest. These results suggest that high expression of FOXM1/B-MYB is critical for sustaining cell proliferation in mtDNA-less cells. In addition, we found that high expression of FOXM1 was mediated by the deubiquitinating enzyme, OTUB1, in one cell line. Thus, interference with FOXM1/B-MYB expression, such as through OTUB1 inhibition, may induce a dormant state of senescence-like proliferation arrest in mtDNA-less cancer cells. This finding may be utilized for the development of precision medicine for relevant cancers.


Assuntos
Carcinoma Hepatocelular/genética , Proliferação de Células/genética , DNA Mitocondrial/genética , Proteína Forkhead Box M1/genética , Neoplasias Hepáticas/genética , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Células Cultivadas , Variações do Número de Cópias de DNA , Regulação Neoplásica da Expressão Gênica , Hepatócitos/metabolismo , Hepatócitos/patologia , Humanos , Neoplasias Hepáticas/patologia , Regulação para Cima/genética
8.
Bioorg Med Chem Lett ; 29(18): 2659-2663, 2019 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-31371134

RESUMO

Reactive oxygen species (ROS) are known to be produced during the amyloid beta (Aß) aggregation process. Both ROS production and Aß fibril formation can result in nerve cell injury. Proanthocyanidins are oligomers of catechin that can act as inhibitors of Aß aggregation. Procyanidin B3 (Cat-Cat), the dimer of (+)-catechin, can easily cross the blood-brain barrier. Previously, we synthesized two derivatives of Cat-Cat, namely Cat-PCat and PCat-PCat, in which the geometry of one or both catechin molecules in Cat-Cat was constrained to be planar. The antioxidative activities of Cat-PCat and PCat-PCat were found to be stronger than that of Cat-Cat, with PCat-PC at exhibiting the most potent activity. These compounds are predicted to protect against Aß-induced neurotoxicity via inhibition of Aß aggregation as well as by antioxidative effects toward Aß-induced intracellular ROS generation. PCat-PCat exhibited the most potent neuroprotective effects against Aß-induced cytotoxicity, which resulted from inhibition of ß-sheet structure formation during the Aß aggregation process. PCat-PCat may be a promising lead compound for the treatment of Alzheimer's disease.


Assuntos
Peptídeos beta-Amiloides/antagonistas & inibidores , Antioxidantes/farmacologia , Biflavonoides/farmacologia , Catequina/farmacologia , Fármacos Neuroprotetores/farmacologia , Proantocianidinas/farmacologia , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Antioxidantes/síntese química , Antioxidantes/química , Biflavonoides/síntese química , Biflavonoides/química , Barreira Hematoencefálica/efeitos dos fármacos , Barreira Hematoencefálica/metabolismo , Catequina/síntese química , Catequina/química , Relação Dose-Resposta a Droga , Humanos , Estrutura Molecular , Fármacos Neuroprotetores/síntese química , Fármacos Neuroprotetores/química , Proantocianidinas/síntese química , Proantocianidinas/química , Agregados Proteicos/efeitos dos fármacos , Espécies Reativas de Oxigênio/antagonistas & inibidores , Espécies Reativas de Oxigênio/metabolismo , Relação Estrutura-Atividade
9.
FEBS J ; 286(3): 459-478, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30281903

RESUMO

Matrix metalloproteinases (MMPs) are tissue-remodeling enzymes involved in the processing of various biological molecules. MMPs also play important roles in cancer metastasis, contributing to angiogenesis, intravasation of tumor cells, and cell migration and invasion. Accordingly, unraveling the signaling pathways controlling MMP activities could shed additional light on cancer biology. Here, we report a molecular axis, comprising the molecular adaptor hydrogen peroxide-inducible clone-5 (HIC-5), NADPH oxidase 4 (NOX4), and mitochondria-associated reactive oxygen species (mtROS), that regulates MMP9 expression and may be a target to suppress cancer metastasis. We found that this axis primarily downregulates mtROS levels which stabilize MMP9 mRNA. Specifically, HIC-5 suppressed the expression of NOX4, the source of the mtROS, thereby decreasing mtROS levels and, consequently, destabilizing MMP9 mRNA. Interestingly, among six cancer cell lines, only EJ-1 and MDA-MB-231 cells exhibited upregulation of NOX4 and MMP9 expression after shRNA-mediated HIC-5 knockdown. In these two cell lines, activating RAS mutations commonly occur, suggesting that the HIC-5-mediated suppression of NOX4 depends on RAS signaling, a hypothesis that was supported experimentally by the introduction of activated RAS into mammary epithelial cells. Notably, HIC-5 knockdown promoted lung metastasis of MDA-MB-231 cancer cells in mice. The tumor growth of HIC-5-silenced MDA-MB-231 cells at the primary sites was comparable to that of control cells. Consistently, the invasive properties of the cells, but not their proliferation, were enhanced by the HIC-5 knockdown in vitro. We conclude that NOX4-mediated mtROS signaling increases MMP9 mRNA stability and affects cancer invasiveness but not tumor growth.


Assuntos
Neoplasias da Mama/genética , Regulação Neoplásica da Expressão Gênica , Peptídeos e Proteínas de Sinalização Intracelular/genética , Proteínas com Domínio LIM/genética , Neoplasias Pulmonares/genética , Mitocôndrias/metabolismo , NADPH Oxidase 4/genética , Espécies Reativas de Oxigênio/metabolismo , Animais , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Senescência Celular , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Matriz Extracelular/metabolismo , Matriz Extracelular/patologia , Feminino , Adesões Focais/metabolismo , Adesões Focais/patologia , Xenoenxertos , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/antagonistas & inibidores , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Proteínas com Domínio LIM/antagonistas & inibidores , Proteínas com Domínio LIM/metabolismo , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/secundário , Metaloproteinase 9 da Matriz/genética , Metaloproteinase 9 da Matriz/metabolismo , Camundongos , Camundongos Endogâmicos NOD , Mitocôndrias/patologia , NADPH Oxidase 4/metabolismo , Invasividade Neoplásica , Estresse Oxidativo , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas B-raf/metabolismo , Proteínas Proto-Oncogênicas p21(ras)/genética , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Transdução de Sinais
10.
Bioorg Med Chem Lett ; 26(22): 5468-5471, 2016 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-27789140

RESUMO

Amyloid-ß (Aß) deposition and oxidative stress observed in the brains of patients with Alzheimer's disease (AD) are important targets for therapeutic intervention. In this study, we conjugated the antioxidants caffeic acid (CA) and dihydrocaffeic acid (DHCA) to Aß1-42 C-terminal motifs (Aßx-42: x=38, 40) to synthesize CA-Aßx-42 and DHCA-Aßx-42, respectively. Among the compounds, CA-Aß38-42 exhibited potent inhibitory activity against Aß1-42 aggregation and scavenged Aß1-42-induced intracellular oxidative stress. Moreover, CA-Aß38-42 significantly protected human neuroblastoma SH-SY5Y cells against Aß1-42-induced cytotoxicity, with an IC50 of 4µM. These results suggest that CA-Aß38-42 might be a potential lead for the treatment of AD.


Assuntos
Peptídeos beta-Amiloides/metabolismo , Peptídeos beta-Amiloides/farmacologia , Amiloide/antagonistas & inibidores , Antioxidantes/farmacologia , Ácidos Cafeicos/farmacologia , Fármacos Neuroprotetores/farmacologia , Fragmentos de Peptídeos/metabolismo , Fragmentos de Peptídeos/farmacologia , Agregados Proteicos/efeitos dos fármacos , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Amiloide/metabolismo , Peptídeos beta-Amiloides/química , Antioxidantes/química , Ácidos Cafeicos/química , Linhagem Celular Tumoral , Humanos , Fármacos Neuroprotetores/química , Estresse Oxidativo/efeitos dos fármacos , Fragmentos de Peptídeos/química
11.
Cancer Sci ; 107(7): 963-71, 2016 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-27094710

RESUMO

Mitochondria are multifunctional organelles; they have been implicated in various aspects of tumorigenesis. In this study, we investigated a novel role of the basal electron transport chain (ETC) activity in cell proliferation by inhibiting mitochondrial replication and transcription (mtR/T) using pharmacological and genetic interventions, which depleted mitochondrial DNA/RNA, thereby inducing ETC deficiency. Interestingly, mtR/T inhibition did not decrease ATP levels despite deficiency in ETC activity in different cell types, including MDA-MB-231 breast cancer cells, but it severely impeded cell cycle progression, specifically progression during G2 and/or M phases in the cancer cells. Under these conditions, the expression of a group of cell cycle regulators was downregulated without affecting the growth signaling pathway. Further analysis suggested that the transcriptional network organized by E2F1 was significantly affected because of the downregulation of E2F1 in response to ETC deficiency, which eventually resulted in the suppression of cell proliferation. Thus, in this study, the E2F1-mediated ETC-dependent mechanism has emerged as the regulatory mechanism of cell cycle progression. In addition to E2F1, FOXM1 and BMYB were also downregulated, which contributed specifically to the defects in G2 and/or M phase progression. Thus, ETC-deficient cancer cells lost their growing ability, including their tumorigenic potential in vivo. ETC deficiency abolished the production of reactive oxygen species (ROS) from the mitochondria and a mitochondria-targeted antioxidant mimicked the deficiency, thereby suggesting that ETC activity signaled through ROS production. In conclusion, this novel coupling between ETC activity and cell cycle progression may be an important mechanism for coordinating cell proliferation and metabolism.


Assuntos
Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Fator de Transcrição E2F1/metabolismo , Redes Reguladoras de Genes , Neoplasias da Mama/genética , Pontos de Checagem do Ciclo Celular , Proteínas de Ciclo Celular/metabolismo , Divisão Celular , Linhagem Celular Tumoral , Proliferação de Células , Inibição de Contato , Proteínas de Ligação a DNA/deficiência , Regulação para Baixo , Transporte de Elétrons/genética , Proteína Forkhead Box M1/metabolismo , Fase G2 , Regulação Neoplásica da Expressão Gênica , Humanos , Proteínas Mitocondriais/deficiência , Fenótipo , Espécies Reativas de Oxigênio/metabolismo , Transativadores/metabolismo , Fatores de Transcrição/deficiência
12.
Gan To Kagaku Ryoho ; 43(12): 2234-2236, 2016 Nov.
Artigo em Japonês | MEDLINE | ID: mdl-28133280

RESUMO

The patient was a 78-year-old woman. She was referred to our hospital and diagnosed with advanced gastric cancer with para-aortic lymph node(#16)metastasis. She received the SOX regimen(L-OHP 100mg/m2)chemotherapy and developed fatigue, anorexia, and neutropenia. After 4 courses of the SOX regimen, the #16 metastasis was reduced remarkably. A curative operation was performed and histological evaluation of the primary and lymphatic lesion after chemotherapy showed Grade 3 findings. The SOX regimen is tolerable in the outpatient clinic and is useful as part of multidisciplinary treatment for advanced gastric cancer.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Gástricas/tratamento farmacológico , Idoso , Combinação de Medicamentos , Feminino , Gastrectomia , Humanos , Metástase Linfática , Terapia Neoadjuvante , Compostos Organoplatínicos/administração & dosagem , Oxaliplatina , Ácido Oxônico/administração & dosagem , Neoplasias Gástricas/patologia , Neoplasias Gástricas/cirurgia , Tegafur/administração & dosagem , Resultado do Tratamento
13.
Gan To Kagaku Ryoho ; 43(12): 1776-1778, 2016 Nov.
Artigo em Japonês | MEDLINE | ID: mdl-28133128

RESUMO

The patient was a 73-year-old man. Upper gastrointestinal endoscopy revealed a type 3 tumor in the antrum of the stomach. Preoperative CT imaging showed multiple liver metastases(S2, S3, S4, S6, S7). We administered 2 courses of chemotherapy( XP therapy)for the unresectable gastric cancer; the impact of the neoadjuvant therapy was PR. We performed distal gastrectomy and D2 dissection. After gastric resection, we administered an additional 3 courses of XP therapy. Unfortunately, new lesions of liver metastases were recurrent at S5 and S8. The patient was treated with 3 courses of S-1 chemotherapy. However, abdominal CT and EOB-MRI revealed significant tumor growth despite S-1 therapy. We performed S5 sub-segment resection and S8 partial resection due to the absence of new lesions. Histopathological findings revealed that the well-differentiated adenocarcinoma had metastasized to the liver, with Grade 1a tumor destruction. Two years after the initial gastrectomy, no recurrence of gastric cancer was observed.


Assuntos
Adenocarcinoma/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Hepáticas/tratamento farmacológico , Terapia Neoadjuvante , Neoplasias Gástricas/tratamento farmacológico , Adenocarcinoma/secundário , Adenocarcinoma/cirurgia , Idoso , Gastrectomia , Hepatectomia , Humanos , Neoplasias Hepáticas/secundário , Neoplasias Hepáticas/cirurgia , Masculino , Neoplasias Gástricas/patologia , Neoplasias Gástricas/cirurgia
14.
ACS Macro Lett ; 5(3): 391-395, 2016 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-35614710

RESUMO

Tin-containing block copolymers were investigated as materials for nanolithographic applications. Poly(4-trimethylstannylstyrene-block-styrene) (PSnS-PS) and poly(4-trimethylstannylstyrene-block-4-methoxystyrene) (PSnS-PMOST) synthesized by reversible addition-fragmentation chain transfer polymerization form lamellar domains with periodicities ranging from 18 to 34 nm. Thin film orientation control was achieved by thermal annealing between a neutral surface treatment and a top coat. Incorporation of tin into one block facilitates pattern transfer into SiO2 via a two-step etch process utilizing oxidative and fluorine-based etch chemistries.

15.
Biochem Biophys Res Commun ; 443(3): 821-7, 2014 Jan 17.
Artigo em Inglês | MEDLINE | ID: mdl-24342608

RESUMO

Transforming growth factor (TGF)-ß is a pro-oncogenic cytokine that induces the epithelial-mesenchymal transition (EMT), a crucial event in tumor progression. During TGF-ß-mediated EMT in NMuMG mouse mammary epithelial cells, we observed sustained increases in reactive oxygen species (ROS) levels in the cytoplasm and mitochondria with a concomitant decrease in mitochondrial membrane potential and intracellular glutathione levels. In pseudo ρ0 cells, whose respiratory chain function was impaired, the increase in intracellular ROS levels was abrogated, suggesting an important role of mitochondrial activity as a trigger for TGF-ß-stimulated ROS generation. In line with this, TGF-ß-mediated expression of the EMT marker fibronectin was inhibited not only by chemicals that interfere with ROS signaling but also by exogenously expressed mitochondrial thioredoxin (TXN2) independent of Smad signaling. Of note, TGF-ß-mediated induction of HMGA2, a central mediator of EMT and metastatic progression, was similarly impaired by TXN2 expression, revealing a novel mechanism involving a thiol oxidation reaction in mitochondria, which regulates TGF-ß-mediated gene expression associated with EMT.


Assuntos
Transição Epitelial-Mesenquimal/genética , Regulação da Expressão Gênica/efeitos dos fármacos , Mitocôndrias/metabolismo , Proteínas Mitocondriais/metabolismo , Tiorredoxinas/metabolismo , Fator de Crescimento Transformador beta/farmacologia , Animais , Linhagem Celular , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Feminino , Células HEK293 , Proteínas HMGA/metabolismo , Humanos , Espaço Intracelular/efeitos dos fármacos , Espaço Intracelular/metabolismo , Glândulas Mamárias Animais/citologia , Camundongos , Mitocôndrias/efeitos dos fármacos , Oxirredução/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética
16.
Ear Nose Throat J ; 92(2): 74-83, 2013 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-23460215

RESUMO

The clinical presentation of calcific retropharyngeal tendinitis, a rare entity, can mimic more serious disorders. We describe the case of a 35-year-old man who was referred to us for evaluation of a suspected retropharyngeal abscess. At presentation, the patient reported severe cervical pain and stiffness. He exhibited mild fever, torticollis, and a moderately elevated white blood count; no swelling of the retropharyngeal wall was observed. Based on the results of plain radiography and computed tomography (CT), we diagnosed the patient with calcific retropharyngeal tendinitis. He was treated with a 7-day course of a nonsteroidal anti-inflammatory drug and a 3-day course of a steroid, and he recovered well. We suggest that the true incidence of calcific retropharyngeal tendinitis is actually higher than what is generally believed because this diagnosis is frequently missed. Contrast-enhanced CT can aid in diagnosing calcific retropharyngeal tendinitis. CT should be performed in patients who present with nonspecific symptoms such as severe neck pain, sore throat, odynophagia, and mild fever.


Assuntos
Calcinose/diagnóstico , Diagnóstico Precoce , Doenças Faríngeas/diagnóstico , Tendinopatia/diagnóstico , Adulto , Anti-Inflamatórios/uso terapêutico , Anti-Inflamatórios não Esteroides/uso terapêutico , Calcinose/tratamento farmacológico , Vértebras Cervicais/patologia , Dexametasona/uso terapêutico , Diagnóstico Diferencial , Diclofenaco/uso terapêutico , Humanos , Masculino , Cervicalgia/etiologia , Doenças Faríngeas/tratamento farmacológico , Faringite/etiologia , Tendinopatia/tratamento farmacológico , Tomografia Computadorizada por Raios X , Torcicolo/etiologia
17.
J Biol Chem ; 287(46): 38854-65, 2012 Nov 09.
Artigo em Inglês | MEDLINE | ID: mdl-23007394

RESUMO

Anchorage loss elicits a set of responses in cells, such as transcriptional changes, in order to prevent inappropriate cell growth in ectopic environments. However, the mechanisms underlying these responses are poorly understood. In this study, we investigated the transcriptional up-regulation of cyclin-dependent kinase inhibitor p21(Cip1) during anchorage loss, which is important for cell cycle arrest of nonadherent cells in the G1 phase. Up-regulation was mediated by an upstream element, designated as the detachment-responsive element (DRE), that contained Kruppel-like factor 4 (KLF4) and runt-related transcription factor 1 (RUNX1) recognition sites; both of these together were necessary for transactivation, as individually they were insufficient. RNAi experiments revealed that KLF4 and a multidomain adaptor protein, hydrogen peroxide-inducible clone 5 (HIC-5), were critically involved in DRE transactivation. The role of HIC-5 in this mechanism was to tether KLF4 to DNA sites in response to cellular detachment. In addition, further analysis suggested that oligomerization and subsequent nuclear matrix localization of HIC-5, which was accelerated spontaneously in cells during anchorage loss, was assumed to potentiate the scaffolding function of HIC-5 in the nucleus and consequently regulate p21(Cip1) transcription in a manner responding to anchorage loss. At the RUNX1 site, a LIM-only protein, CRP2, imposed negative regulation on transcription, which appeared to be removed by anchorage loss and contributed to increased transcriptional activity of DRE together with regulation at the KLF4 sites. In conclusion, this study revealed a novel transcriptional mechanism that regulated gene expression in a detachment-dependent manner, thereby contributing to anchorage-dependent cell growth.


Assuntos
Inibidor de Quinase Dependente de Ciclina p21/metabolismo , Proteínas do Citoesqueleto/metabolismo , Proteínas de Ligação a DNA/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Fatores de Transcrição Kruppel-Like/metabolismo , Proteínas com Domínio LIM/metabolismo , Ativação Transcricional , Animais , Sítios de Ligação , Adesão Celular , DNA/química , Fibroblastos/metabolismo , Regulação da Expressão Gênica , Células HEK293 , Humanos , Fator 4 Semelhante a Kruppel , Camundongos , Camundongos Endogâmicos C3H , Modelos Biológicos , Ligação Proteica , Frações Subcelulares
18.
Cancer Sci ; 103(10): 1803-10, 2012 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-22726539

RESUMO

In most human cancers, somatic mutations have been identified in the mtDNA; however, their significance remains unclear. We recently discovered that NMuMG mouse mammary epithelial cells, when deprived of mitochondria or following inhibition of respiratory activity, undergo epithelial morphological disruption accompanied with irregular edging of E-cadherin, the appearance of actin stress fibers, and an altered gene expression profile. In this study, using the mtDNA-less pseudo ρ0 cells obtained from NMuMG mouse mammary epithelial cells, we examined the roles of two mitochondrial stress-associated transcription factors, cAMP-responsive element-binding protein (CREB) and C/EBP homologous protein-10 (CHOP), in the disorganization of epithelial phenotypes. We found that the expression of matrix metalloproteinase-13 and that of GADD45A, SNAIL and integrin α1 in the ρ0 cells were regulated by CHOP and CREB, respectively. Of note, knockdown and pharmacological inhibition of CREB ameliorated the disrupted epithelial morphology. It is interesting to note that the expression of high mobility group AT-hook 2 (HMGA2), a non-histone chromatin protein implicated in malignant neoplasms, was increased at the protein level through the CREB pathway. Here, we reveal how the activation of the CREB/HMGA2 pathway is implicated in the repression of integrin α1 expression in HepG2 human cancer cells, highlighting the importance of the CREB/HMGA2 pathway in malignant transformation associated with mitochondrial dysfunction, thereby raising the possibility that the pathway indirectly interferes with the cell-cell adhesion structure by influencing the cell-extracellular matrix adhesion status. Overall, the data suggest that mitochondrial dysfunction potentially contributes to neoplastic transformation of epithelial cells through the activation of these transcriptional pathways.


Assuntos
Transformação Celular Neoplásica/metabolismo , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Mitocôndrias/patologia , Animais , Western Blotting , Linhagem Celular Tumoral , DNA Mitocondrial/metabolismo , Proteína HMGA2/metabolismo , Humanos , Camundongos , Mitocôndrias/metabolismo , Fenótipo , Reação em Cadeia da Polimerase em Tempo Real , Transdução de Sinais/fisiologia
19.
Acta Radiol ; 53(3): 303-6, 2012 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-22287150

RESUMO

BACKGROUND: Carcinoma ex pleomorphic adenoma (CXPA) is a rare aggressive epithelial malignancy arising from a primary or recurrent benign mixed tumor. Only a few case reports describing the radiologic features of CXPA have been published. PURPOSE: To describe and characterize the magnetic resonance (MR) imaging findings of CXPA in the parotid gland and correlate them with pathologic findings. MATERIAL AND METHODS: The MR images of surgically proven CXPA in the parotid gland of five men and five women ranging in age from 28 to 75 years (mean 52 years) were retrospectively reviewed. All MR images were evaluated with emphasis on the size, margin characteristics, extraparotid infiltration, the presence of an encapsulated component, and signal intensity on T2-weighted or short-inversion-time inversion recovery (STIR) images. RESULTS: The average maximal diameter was 4.3 cm. All 10 tumors had ill-defined boundaries, and seven tumors showed extraparotid infiltration, reflecting invasive growth of the malignant component identified on histological examination. Eight tumors had a round encapsulated component and seven of those signal intensities were a mixture of hypo- and hyperintensity on T2-weighted or STIR images. Histological correlation of these components revealed fibrously encapsulated tumors containing hyalinization and myxoid tissue, suggesting degenerated pleomorphic adenoma. Invasive malignant components had non-specific and various signal intensities. CONCLUSION: An invasive parotid mass co-existing with a round encapsulated component is suggestive of carcinoma ex pleomorphic adenoma.


Assuntos
Adenoma Pleomorfo/patologia , Neoplasias Parotídeas/patologia , Adulto , Idoso , Biópsia por Agulha , Diagnóstico Diferencial , Imagem de Difusão por Ressonância Magnética/métodos , Feminino , Humanos , Imageamento por Ressonância Magnética/métodos , Masculino , Pessoa de Meia-Idade , Variações Dependentes do Observador , Glândula Parótida/patologia , Reprodutibilidade dos Testes , Estudos Retrospectivos
20.
Int J Cell Biol ; 2012: 426138, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22145007

RESUMO

HIC-5 is a multidomain LIM protein homologous to paxillin that serves as a molecular scaffold at focal adhesions and in the nucleus. It forms mobile molecular units with LIM-only proteins, PINCH, and CRP2 and translocates in and out of the nucleus via a nuclear export signal (NES). Of note, NES of HIC-5 is distinctive in its sensitivity to the cellular redox state. Recently, the mobile units of HIC-5 have been suggested to be involved in the regulation of the anchorage dependence of cell growth. On loss of adhesion, an increase in reactive oxygen species in the cells modifies NES and stops shuttling, which leads to cell-cycle control. More specifically, the system circumvents nuclear localization of cyclin D1 and transactivates p21(Cip1) in detached cells, thereby avoiding anchorage-independent cell growth. Thus, the HIC-5-LIM only protein complex has emerged as a fail-safe system for regulating the anchorage dependence of cell growth.

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