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1.
J Biol Chem ; 294(17): 6871-6887, 2019 Apr 26.
Artigo em Inglês | MEDLINE | ID: mdl-30824540

RESUMO

EPHB6 is a member of the erythropoietin-producing hepatocellular kinase (EPH) family and a receptor tyrosine kinase with a dead kinase domain. It is involved in blood pressure regulation and adrenal gland catecholamine (CAT) secretion, but several facets of EPHB6-mediated CAT regulation are unclear. In this study, using biochemical, quantitative RT-PCR, immunoblotting, and gene microarray assays, we found that EPHB6 up-regulates CAT biosynthesis in adrenal gland chromaffin cells (AGCCs). We observed that epinephrine content is reduced in the AGCCs from male Ephb6-KO mice, caused by decreased expression of tyrosine hydroxylase, the rate-limiting enzyme in CAT biosynthesis. We demonstrate that the signaling pathway from EPHB6 to tyrosine hydroxylase expression in AGCCs involves Rac family small GTPase 1 (RAC1), MAP kinase kinase 7 (MKK7), c-Jun N-terminal kinase (JNK), proto-oncogene c-Jun, activator protein 1 (AP1), and early growth response 1 (EGR1). On the other hand, signaling via extracellular signal-regulated kinase (ERK1/2), p38 mitogen-activated protein kinase, and ELK1, ETS transcription factor (ELK1) was not affected by EPHB6 deletion. We further report that EPHB6's effect on AGCCs was via reverse signaling through ephrin B1 and that EPHB6 acted in concert with the nongenomic effect of testosterone to control CAT biosynthesis. Our findings elucidate the mechanisms by which EPHB6 modulates CAT biosynthesis and identify potential therapeutic targets for diseases, such as hypertension, caused by dysfunctional CAT biosynthesis.

2.
Int J Oncol ; 54(1): 188-198, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30387835

RESUMO

Renal cell carcinoma (RCC), which is a type of cancer found in the kidney tubule, is among the 10 most frequently occurring human cancers. Regucalcin plays a potential role as a regulator of transcriptional activity, and its downregulated expression or activity may contribute to the promotion of human cancers. In this study, we investigated the involvement of regucalcin in human RCC. Regucalcin expression was compared in 23 normal and 29 tumor samples of kidney cortex tissues of patients with clear cell RCC obtained through the Gene Expression Omnibus (GEO) database (GSE36895). Regucalcin expression was downregulated in the tumor tissues. The prolonged survival of patients with clear cell RCC was demonstrated to be associated with a higher regucalcin gene expression in the TCGA dataset. The overexpression of regucalcin suppressed the colony formation, proliferation and the death of human clear cell RCC A498 cells in vitro. Mechanistically, the overexpression of regucalcin induced the G1 and G2/M phase cell cycle arrest of A498 cells through the suppression of multiple signaling components, including Ras, PI3 kinase, Akt and mitogen­activated protein (MAP) kinase. Importantly, the overexpression of regucalcin led to an elevation in the levels of the tumor suppressors, p53, Rb and the cell cycle inhibitor, p21. The levels of the transcription factors, c­fos, c­jun, nuclear factor­κB p65, ß­catenin and signal transducer and activator of transcription 3, were suppressed by regucalcin overexpression. On the whole, the findings of this study suggest that regucalcin plays a suppressive role in the promotion of human RCC. The overexpression of regucalcin by gene delivery systems may thus prove to be a novel therapeutic strategy for RCC.


Assuntos
Proteínas de Ligação ao Cálcio/genética , Carcinoma de Células Renais/genética , Peptídeos e Proteínas de Sinalização Intracelular/genética , Neoplasias Renais/genética , Regulação para Cima , Pontos de Checagem do Ciclo Celular , Linhagem Celular Tumoral , Proliferação de Células , Sobrevivência Celular , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Técnicas In Vitro , Transdução de Sinais , Análise de Sobrevida
3.
Int J Oncol ; 53(3): 1313-1322, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29956741

RESUMO

Regucalcin plays a crucial role as a regulator of transcriptional signaling activity, and its decreased expression or activity may contribute to the promotion of human carcinogenesis. A higher regucalcin expression in the tumor tissues has been demonstrated to prolong the survival of patients with various types of cancer, including pancreatic cancer, breast cancer, liver cancer and lung adenocarcinoma. The involvement of regucalcin in human colorectal cancer was investigated in the current study. Regucalcin gene expression and the survival data of 62 patients with colorectal cancer were obtained though the Gene Expression Omnibus (GEO) database (GSE12945) for outcome analysis. The data of gene expression revealed that the prolonged survival of patients with colorectal cancer was associated with a higher regucalcin gene expression in tumor tissues. The overexpression of regucalcin suppressed colony formation and proliferation, and induced the death of human colorectal carcinoma RKO cells cultured in a medium containing fetal bovine serum in vitro. Mechanistically, the overexpression of regucalcin induced the G1 and G2/M phase cell cycle arrest of the RKO cells through the suppression of multiple signaling pathways, including Ras, Akt, mitogen-activated protein (MAP) kinase and SAPK/JNK. Of note, the overexpression of regucalcin induced an increase in the levels of the tumor suppressors, p53 and Rb, and the cell cycle inhibitor, p21. Moreover, the levels of the transcription factors, c­fos, c­jun, nuclear factor (NF)­κB p65, ß-catenin and signal transducer and activator of transcription 3 (Stat3), were suppressed by the overexpression of regucalcin. On the whole, the findings of this study suggest that regucalcin plays a crucial role as a suppressor in human colorectal cancer, and that the suppressed expression of the regucalcin gene may predispose patients to the promotion of colorectal cancer. The overexpression of regucalcin by gene delivery may thus prove to be a novel therapeutic strategy for colorectal cancer.


Assuntos
Proteínas de Ligação ao Cálcio/metabolismo , Proliferação de Células/genética , Neoplasias Colorretais/patologia , Regulação Neoplásica da Expressão Gênica , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Proteínas Supressoras de Tumor/metabolismo , Adulto , Animais , Proteínas de Ligação ao Cálcio/genética , Carcinogênese/genética , Pontos de Checagem do Ciclo Celular/genética , Linhagem Celular Tumoral , Neoplasias Colorretais/mortalidade , Conjuntos de Dados como Assunto , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Masculino , Transdução de Sinais/genética , Análise de Sobrevida , Proteínas Supressoras de Tumor/genética
4.
Oncol Rep ; 39(6): 2924-2930, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29620227

RESUMO

Regucalcin, which its gene is localized on the X chromosome, plays a pivotal role as a suppressor protein in signal transduction in various types of cells and tissues. Regucalcin gene expression has been demonstrated to be suppressed in various tumor tissues of animal and human subjects, suggesting a potential role of regucalcin in carcinogenesis. Regucalcin, which is produced from the tissues including liver, is found to be present in the serum of human subjects and animals. This study was undertaken to determine the effects of exogenous regucalcin on the proliferation in cloned human hepatoma HepG2 cells in vitro. Proliferation of HepG2 cells was suppressed after culture with addition of regucalcin (0.01 – 10 nM) into culture medium. Exogenous regucalcin did not reveal apoptotic cell death in HepG2 cells in vitro. Suppressive effects of regucalcin on cell proliferation were not enhanced in the presence of various signaling inhibitors including tumor necrosis factor-α (TNF-α), Bay K 8644, PD98059, staurosporine, worthomannin, 5,6-dichloro-1-β-D-ribofuranosylbenzimidazole (DRB) or gemcitabine, which were found to suppress the proliferation. In addition, exogenous regucalcin suppressed the formation of colonies of cultured hepatoma cells in vitro. These findings demonstrated that exogenous regucalcin exhibits a suppressive effect on the growth of human hepatoma HepG2 cells, proposing a strategy with the gene therapy for cancer treatment.


Assuntos
Proteínas de Ligação ao Cálcio/farmacologia , Peptídeos e Proteínas de Sinalização Intracelular/farmacologia , Neoplasias Hepáticas/metabolismo , Animais , Apoptose , Proteínas de Ligação ao Cálcio/sangue , Proliferação de Células/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Regulação Neoplásica da Expressão Gênica , Células Hep G2 , Humanos , Técnicas In Vitro , Peptídeos e Proteínas de Sinalização Intracelular/sangue , Neoplasias Hepáticas/tratamento farmacológico , Ratos
5.
FEBS Open Bio ; 8(3): 349-360, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29511612

RESUMO

Amyloid-ß (Aß), a primary component of amyloid plaques, has been widely associated with the pathogenesis of Alzheimer's disease. The Ca2+-binding protein regucalcin (RGN) plays multiple roles in maintaining cell functions by regulating intracellular calcium homeostasis, various signaling pathways, and gene expression systems. Here, we investigated the functional role of RGN against Aß-induced cytotoxicity in neuronally differentiated PC12 cells. Overexpression of RGN reduced Aß-induced apoptosis by reducing mitochondrial dysfunction and caspase activation. It also attenuated Aß-induced reactive oxygen species production and oxidative damage and decreased Aß-induced nitric oxide (NO) overproduction, upregulation of inducible NO synthase by nuclear factor-κB, and nitrosative damage. Interestingly, the genetic disruption of RGN increased the susceptibility of neuronally differentiated PC12 cells to Aß toxicity. Thus, RGN possesses antioxidant activity against Aß-induced oxidative and nitrosative stress and may play protective roles against Aß-induced neurotoxicity in Alzheimer's disease.

6.
J Nat Med ; 72(1): 260-266, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29151157

RESUMO

Erypoegin K is an isoflavone isolated from the stem bark of Erythrina poeppigiana. It contains a furan group at the A-ring of the core isoflavone structure and can inhibit the activity of glyoxalase I, an enzyme that catalyzes the detoxification of methylglyoxal (MG), a by-product of glycolysis. In the present study, we found that erypoegin K has a potent cytotoxic effect on human leukemia HL-60 cells. Its cytotoxic effect was much stronger than that of a known glyoxalase I inhibitor S-p-bromobenzylglutathione cyclopentyl diester. Conversely, erypoegin K demonstrated weak cytotoxicity toward normal human peripheral lymphocytes. The treatment of HL-60 cells with erypoegin K significantly induced caspase-3 activity, whereas the pretreatment of the cells with caspase-3 inhibitor suppressed erypoegin K-induced cell death. Furthermore, nuclear condensation and apoptotic genome DNA fragmentation were observed in erypoegin K-treated HL-60 cells. These results indicated that the observed cell death was mediated by apoptosis. In addition, the toxic compound MG was highly accumulated in the culture medium of erypoegin K-treated HL-60 cells, suggesting that cell apoptosis was triggered by extracellular MG. The present study showed that erypoegin K has a potent apoptosis-inducing effect on cancerous cell lines, such as HL-60.


Assuntos
Benzofuranos/química , Erythrina/química , Células HL-60/química , Isoflavonas/química , Leucemia/tratamento farmacológico , Apoptose , Humanos , Leucemia/patologia
7.
Mol Med Rep ; 17(2): 3432, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29257315

RESUMO

Following the publication of this article, the authors noted that Fig. 1 appeared incorrectly in the journal. Essentially, the figure was reorganized but only the labels for Fig. 1B and C were switched around, with the result that Fig. 1B and C were labelled incorrectly in the paper. The corrected figure is shown here, with the figure parts for Fig. 1B and C now labelled correctly. This error was introduced into the figure during the pre-press stages. The editorial office wishes to apologize to the authors for this mistake, and we regret the inconvenience this mistake has caused. [the original article was published in the Molecular Medicine Reports 12: 7801-7805, 2015; DOI: 0.3892/mmr.2015.4352].

8.
Biomed Rep ; 6(4): 374-378, 2017 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-28413634

RESUMO

Regucalcin gene promoter region-related protein-p117 (RGPR-p117; gene symbol, rgpr-117) was identified in 2001 as a novel transcription factor that specifically binds to a nuclear factor I consensus motif, TTGGC(N)6CC in the promoter region of the regucalcin (rgn) gene. The human RGPR-p117 gene consists of 26 exons spanning ~4.1 kbp and is localized on chromosome 1q25.2. The nuclear translocation of cytoplasm RGPR-p117 is mediated via the protein kinase C-dependent signaling pathway. Overexpression of RGPR-p117 enhances the transcription activity of rgn, and a protective effect on cell death by inhibition of gene expression levels of caspase-3, caspase-8 and FADD proteins that possess the TTGGC motif in the promoter region of those genes was revealed. RGPR-p117 has a crucial role as a transcription factor. Notably, RGPR-p117 was shown to localize in the plasma membranes, mitochondria and microsomes (endoplasmic reticulum; ER). RGPR-p117, which is located in the ER, was also shown to have a role as an ER export factor implicated in the transports of proteins and lipids. As a result of this finding, it was proposed in 2007 that RGPR-p117 is renamed SEC 16 homolog B, endoplasmic reticulum export factor (SEC16B). Recently, there is increasing evidence that RGPR-p117/SEC16B may be involved in human obesity. Thus, the current review presents data regarding the involvement of RGPR-p117 in human obesity.

9.
Mol Cell Biochem ; 430(1-2): 37-46, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28181135

RESUMO

Regucalcin plays a crucial role as a suppressor of transcription signaling, and its diminished expression or activity may play a key role in human carcinogenesis. Higher regucalcin expression has been demonstrated to prolong survival of the patients of pancreatic cancer, breast cancer, and hepatocellular carcinoma. Moreover, we investigated an involvement of regucalcin in human lung cancer. Human non-small cell lung cancer (NSCLC) accounts for over 80% in human lung cancer and is one of the leading causes of malignancy-related mortality with fewer than 16% patients surviving beyond 5 years. In this study, gene expression and survival data of 204 lung adenocarcinoma patients were obtained through the gene expression omnibus database (GSE31210) for outcome analysis. Gene expression data demonstrated that prolonged survival in lung cancer patients is associated with higher regucalcin gene expression. Overexpression of regucalcin suppressed the proliferation, cell death, and migration of human lung adenocarcinoma NSCLC A549 cells in vitro. Mechanistically, regucalcin induced G1 and G2/M phase cell cycle arrest of A549 cells through suppression of multiple signaling pathways including Ras, Akt, MAP kinase, and SAPK/JNK. Moreover, overexpression of regucalcin caused decreases in the oncogenes c-fos and c-myc and elevation of the tumor suppressers p53 and Rb. These findings suggest that regucalcin may play a potential role as a suppressor of human lung cancer, and that downregulation of regucalcin expression may predispose patients to development of lung cancer. Overexpression of regucalcin using gene delivery may constitute a novel therapeutic approach to treating lung cancer.


Assuntos
Adenocarcinoma , Proteínas de Ligação ao Cálcio/biossíntese , Proliferação de Células , Regulação Neoplásica da Expressão Gênica , Peptídeos e Proteínas de Sinalização Intracelular/biossíntese , Neoplasias Pulmonares , Proteínas Supressoras de Tumor/biossíntese , Células A549 , Adenocarcinoma/metabolismo , Adenocarcinoma/mortalidade , Adenocarcinoma/patologia , Intervalo Livre de Doença , Feminino , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Masculino , Taxa de Sobrevida
10.
Int J Oncol ; 49(4): 1686-94, 2016 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-27633001

RESUMO

Hepatocellular carcinoma (HCC) is one of the most common malignant cancers worldwide and ranks third in overall global cancer-related mortality rates. Importantly, in this study gene expression data demonstrate that prolonged survival in HCC patients is associated with increased regucalcin gene expression. Regucalcin has been shown to play a pivotal role as a transcription repressor and diminished expression or activity of regucalcin may play a key role in the development of human carcinogenesis. Indeed, overexpression of regucalcin suppressed the proliferation, cell death, and migration of human HCC HepG2 cells in vitro. Mechanistically, regucalcin induced G1 and G2/M phase cell cycle arrest of HepG2 cells through suppression of multiple signaling pathways including Ras, Akt, MAP kinase and SAPK/JNK and by increasing the tumor suppressors p53 and Rb. Furthermore, the oncogenes c-fos and c-myc were suppressed by overexpression of regucalcin, and overexpression of regucalcin caused an increase in p21 and a decrease in NF-κB p65 and ß-catenin. These findings suggest that regucalcin may play a potential role as a suppressor of human HCC, and that diminished expression of regucalcin may predispose patients to development of HCC. Overexpression of regucalcin may constitute a novel therapeutic approach to treating HCC.


Assuntos
Biomarcadores Tumorais/metabolismo , Proteínas de Ligação ao Cálcio/metabolismo , Carcinoma Hepatocelular/mortalidade , Proliferação de Células , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Neoplasias Hepáticas/mortalidade , Apoptose , Biomarcadores Tumorais/genética , Western Blotting , Proteínas de Ligação ao Cálcio/genética , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Movimento Celular , Regulação Neoplásica da Expressão Gênica , Humanos , Técnicas In Vitro , Peptídeos e Proteínas de Sinalização Intracelular/genética , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Células Tumorais Cultivadas
11.
Oncol Lett ; 12(2): 1605-1609, 2016 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-27446479

RESUMO

Gentian violet (GV), a cationic triphenylmethane dye, is used as an antifungal and antibacterial agent. Recently, attention has been focused on GV as a potential chemotherapeutic and antiangiogenic agent. The present study was undertaken to determine the suppressive effects of GV on human breast cancer MDA-MB-231 cells in vitro. The proliferation of MDA-MB-231 cells was suppressed by culture with GV (1-200 nM). The suppressive effects of GV on cell proliferation were not potentiated in the presence of various inhibitors that induce cell cycle arrest in vitro. This finding suggested that GV inhibits G1 and G2/M phase cell cycle arrest in MDA-MB-231 cells. The suppressive effects of GV on proliferation are mediated through the inhibition of various signaling pathways or nuclear transcription in vitro. Moreover, the suppressive effects of GV on cell proliferation were compared with that of gemcitabine, a strong antitumor agent that induces nuclear DNA damage. Notably, the culture with gemcitabine >50 nM suppressed cell proliferation, while the effects of GV were observed at >1 nM. The suppressive effects of gemcitabine on cell proliferation were not potentiated by GV. Overall, the present study demonstrated that GV exhibits a potential suppressive effect on the proliferation of human breast cancer MDA-MB-231 cells in vitro.

12.
Int J Oncol ; 49(2): 812-22, 2016 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-27221776

RESUMO

Human breast cancer is highly metastatic to bone and drives bone turnover. Breast cancer metastases cause osteolytic lesions and skeletal damage that leads to bone fractures. Regucalcin, which plays a pivotal role as an inhibitor of signal transduction and transcription activity, has been suggested to act as a suppressor of human cancer. In the present study, we compared the clinical outcome between 44 breast cancer patients with higher regucalcin expression and 43 patients with lower regucalcin expression. Prolonged relapse-free survival was identified in the patients with increased regucalcin gene expression. We further demonstrated that overexpression of full length, but not alternatively spliced variants of regucalcin, induces G1 and G2/M phase cell cycle arrest, suppressing the proliferation of MDA-MB-231 cells, a commonly used in vitro model of human breast cancer that metastasize to bone causing osteolytic lesions. Overexpression of regucalcin was found to suppress multiple signaling pathways including Akt, MAP kinase and SAPK/JNK, and NF-κB p65 and ß-catenin along with increased p53, a tumor suppressor, and decreased K-ras, c-fos and c-jun. Moreover, we found that co-culture of regucalcin-overexpressing MDA-MB-231 cells with mouse bone marrow cells prevented enhanced osteoclastogenesis and suppressed mineralization in mouse bone marrow cells in vitro. Taken together, the present study suggests that regucalcin may have important anticancer properties in human breast cancer patients. Mechanistically, these effects are likely mediated through suppression of multiple signaling pathways, upregulation of p53 and downregulation of oncogenes leading to anti-proliferative effects and reduced metastases to bone, a phenotype associated with poor clinical outcome.


Assuntos
Neoplasias Ósseas/genética , Neoplasias da Mama/genética , Proteínas de Ligação ao Cálcio/biossíntese , Peptídeos e Proteínas de Sinalização Intracelular/biossíntese , Proteínas de Neoplasias/biossíntese , Animais , Neoplasias Ósseas/patologia , Neoplasias Ósseas/secundário , Neoplasias da Mama/patologia , Proteínas de Ligação ao Cálcio/genética , Diferenciação Celular/genética , Linhagem Celular Tumoral , Proliferação de Células/genética , Técnicas de Cocultura , Intervalo Livre de Doença , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Camundongos , Metástase Neoplásica , Transdução de Sinais/genética , Ensaios Antitumorais Modelo de Xenoenxerto
13.
Int J Oncol ; 48(5): 1955-64, 2016 May.
Artigo em Inglês | MEDLINE | ID: mdl-26935290

RESUMO

Approximately 90% of all pancreatic cancers are pancreatic ductal adenocarcinomas (PDAC). PDAC is a highly aggressive malignancy and is one of the deadliest. This poor clinical outcome is due to the prominent resistance of pancreatic cancer to drug and radiation therapies. Regucalcin plays a pivotal role as a suppressor protein in signal transduction in various types of cells including tumor tissues. We demonstrated that the prolonged survival is induced in PDAC patients with increased regucalcin gene expression using a dataset of PDAC obtained from GEO database (GSE17891) together with the clinical annotation data file. Moreover, overexpression of regucalcin with full length was demonstrated to suppress the proliferation, cell death and migration in human pancreatic cancer MIA PaCa-2 (K-ras mutated) cells that possess resistance to drug and radiation therapies. Suppressive effects of regucalcin on cell proliferation and death were not seen in the cells overexpressed with regucalcin cDNA alternatively spliced variants (deleted exon 4 or deleted exon 4 and 5). Regucalcin was suggested to induce G1 and G2/M phase cell cycle arrest in MIA PaCa-2 cells. Suppressive effects of regucalcin on cell proliferation were independent of cell death. Overexpression of regucalcin was found to suppress signaling pathways including Akt, MAP kinase and SAPK/JNK, to increase the protein levels of p53, a tumor suppresser, and to decrease K-ras, c-fos and c-jun, a oncogene, by suppressing signaling pathways that are related to signaling of K-ras. Regucalcin may play a potential role as a suppressor protein in human pancreatic cancer.


Assuntos
Proteínas de Ligação ao Cálcio/genética , Proteínas de Ligação ao Cálcio/metabolismo , Carcinoma Ductal Pancreático/patologia , Peptídeos e Proteínas de Sinalização Intracelular/genética , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Neoplasias Pancreáticas/patologia , Regulação para Cima , Carcinoma Ductal Pancreático/metabolismo , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Bases de Dados Genéticas , Regulação Neoplásica da Expressão Gênica , Humanos , Técnicas In Vitro , Sistema de Sinalização das MAP Quinases , Neoplasias Pancreáticas/metabolismo , Prognóstico , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Análise de Sobrevida
14.
Nat Prod Commun ; 10(9): 1581-4, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-26594764

RESUMO

It has been reported that many malignant human tissues, including breast, colon, and lung cancers, may show an elevated expression of glyoxalase I (GLO I). GLO I catalyzes the reaction to transform hemimercaptal, a compound formed from methylglyoxal (MG) and reduced glutathione, into S-D-lactoylglutathione, which is then converted to D-lactic acid by glyoxalase II. GLO I inhibitors are expected to be useful for inhibiting tumorigenesis through the accumulation of apoptosis-inducible MG in tumor cells. Here, we investigated the anti-proliferative activity of eight kinds of isoflavone isolated from Erythrina poeppigiana against the growth of HL-60 human leukemia cells from the viewpoint of GLO I inhibition. Of the compounds tested, the diprenyl isoflavone, isolupalbigenin, was shown to exhibit the highest anti-proliferative activity against HL-60 cells. Upon the treatment of HL-60 cells with isolupalbigenin, MG was significantly accumulated in the culture medium, and the caspase 3 activity of the cell lysate was elevated in a time-dependent manner. Thus, it is suggested that isolupalbigenin inhibits the enzyme GLO I, resulting in MG accumulation in the medium, and leading to cell apoptosis. Isolupalbigenin, with two prenyl groups in its A- and B-rings, might be expected to become a potent leading compound for the development of anticancer agents.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Erythrina/química , Isoflavonas/farmacologia , Lactoilglutationa Liase/antagonistas & inibidores , Lactoilglutationa Liase/metabolismo , Antineoplásicos Fitogênicos/química , Sobrevivência Celular , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Regulação Enzimológica da Expressão Gênica , Células HL-60 , Humanos , Isoflavonas/química , Lactoilglutationa Liase/genética , Estrutura Molecular
15.
Oncol Rep ; 34(6): 3304-10, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26397991

RESUMO

Pancreatic cancer is a highly aggressive malignancy with a notoriously dismal prognosis. A major contributor to this poor clinical outcome is pancreatic cancer's prominent chemoresistance. The present study was undertaken to determine whether the flavonoid p­hydroxycinnamic acid (HCA), which is a botanical factor, possesses anticancer effects on cloned human pancreatic cancer MIA PaCa­2 cells that possess resistance to radiation therapy in vitro. Proliferation of MIA PaCa­2 cells was suppressed after culture with HCA (10­1,000 nM). Such an effect was also noted in human pancreatic cancer Pt45P1 cells. In the MIA PaCa­2 cells, HCA induced G1 and G2/M phase cell cycle arrest in the cells. The suppressive effects of HCA on proliferation were suggested to be mediated through the inhibition of various signaling pathways related to nuclear factor­κB (NF­κB), extracellular signal­regulated kinase (ERK), protein kinase C, phosphatidylinositol 3­kinase (PI3K) or nuclear transcription activity. Moreover, HCA was found to stimulate cell death in the MIA PaCa­2 and Pt45P1 cells in vitro. The anticancer effects of HCA on MIA PaCa­2 cells were exhibited at a lower concentration than gemcitabine, a potent cancer drug. The flavonoid HCA may be a useful tool in the therapy of human pancreatic cancer in vivo.


Assuntos
Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Ácidos Cumáricos/administração & dosagem , Neoplasias Pancreáticas/tratamento farmacológico , Apoptose/efeitos da radiação , Linhagem Celular Tumoral , Proliferação de Células/efeitos da radiação , Sobrevivência Celular/efeitos dos fármacos , Desoxicitidina/administração & dosagem , Desoxicitidina/análogos & derivados , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , MAP Quinases Reguladas por Sinal Extracelular , Flavonoides/administração & dosagem , Humanos , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/radioterapia , Fosfatidilinositol 3-Quinases/genética , Tolerância a Radiação/efeitos dos fármacos , Tolerância a Radiação/genética , Transdução de Sinais/efeitos dos fármacos
16.
Mol Med Rep ; 12(5): 7801-5, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26398369

RESUMO

Regucalcin serves a pivotal role as a suppressor protein in signal transduction in various types of cells and tissues. The regucalcin gene, which is localized on the X chromosome, consists of seven exons and six introns. Reductions in the gene expression of regucalcin have been suggested to serve a role in hepatocarcinogenesis in animal models and human patients, indicating a potential role as a suppressor protein in cancer. The aim of the current study was to investigate the effect of exogenous regucalcin on cell proliferation in the cloned human breast cancer MDA­MB­231 bone metastatic cell line in vitro. The proliferation of MDA­MB­231 cells was suppressed following the addition of regucalcin (0.1­10 nM) in vitro. The suppression of proliferation was not enhanced in the presence of tumor necrosis factor­α, PD98059, staurosporine, Bay K8644, wortmannin, 5,6­dichloro­1­ß­D­ribofuranosylbenzimidazole or gemcitabine. Exogenous regucalcin did not induce cell death in MDA­MB­231 cells in vitro. These data suggest that exogenous regucalcin possesses suppressive effects on the proliferation of human breast cancer MDA­MB­231 bone metastatic cells, and that this effect may be mediated through various intracellular signaling pathways in vitro. Exogenous regucalcin is suggested to function as a suppressor in cancer cell proliferation.


Assuntos
Antineoplásicos/farmacologia , Neoplasias Ósseas/tratamento farmacológico , Neoplasias Ósseas/secundário , Osso e Ossos/patologia , Neoplasias da Mama/tratamento farmacológico , Mama/patologia , Proteínas de Ligação ao Cálcio/farmacologia , Proliferação de Células/efeitos dos fármacos , Peptídeos e Proteínas de Sinalização Intracelular/farmacologia , Animais , Antineoplásicos/isolamento & purificação , Neoplasias Ósseas/patologia , Osso e Ossos/efeitos dos fármacos , Mama/efeitos dos fármacos , Neoplasias da Mama/patologia , Proteínas de Ligação ao Cálcio/isolamento & purificação , Linhagem Celular Tumoral , Feminino , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/isolamento & purificação , Ratos
17.
Int J Oncol ; 47(4): 1563-71, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26238204

RESUMO

Tumor invasion into bone tissues is associated with osteoclast and osteoblast recruitment, resulting in the liberation of growth factors from the bone matrix, which can feed back to enhance tumor growth resulting in the vicious cycle of bone metastasis. Activated nuclear factor-κB (NF-κB) in breast cancer cells has been shown to play a crucial role in the osteolytic bone metastasis of breast cancer in stimulating osteoclastogenesis. The flavonoid p-hydroxycinnamic acid (HCA) mediates bone anabolic and anti-catabolic effects by stimulating osteoblastic bone formation and suppressing osteoclastic bone resorption. However, the capacity of HCA to ameliorate the negative effects of breast cancer on bone cells has not been investigated. The present study was undertaken to determine the anticancer effects of HCA on MDA-MB-231 human breast cancer bone metastatic cells in vitro models. Proliferation of MDA-MB­231 cells was suppressed by culture with HCA (10-1000 nM) due to G1 and G2/M phase cell cycle arrest. The suppressive effects of HCA were mediated through signaling pathways that are related to NF-κB, extracellular signal-regulated kinase (ERK), protein kinase C, calcium signaling, phosphatidylinositol 3-kinase (PI3K) and nuclear transcription activity. HCA was also found to induce death of confluent cancer cells. Furthermore, co-culture with MDA-MB-231 cells suppressed mineralization and stimulated osteoclastogenesis in bone marrow cells. These alterations were prevented by HCA (10-250 nM). The present study demonstrates that HCA possesses anticancer properties in MDA-MB-231 human breast cancer cells and alleviates the negative effects on osteoblastogenesis and osteoclastogenesis in vitro. HCA may have important applications in the treatment of breast cancer bone metastasis.


Assuntos
Antineoplásicos/farmacologia , Neoplasias Ósseas/secundário , Neoplasias da Mama/patologia , Ácidos Cumáricos/farmacologia , Osteogênese/efeitos dos fármacos , Animais , Células da Medula Óssea/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Técnicas de Cocultura , Feminino , Humanos , Técnicas In Vitro , Camundongos , Metástase Neoplásica/patologia , Propionatos , Transdução de Sinais/efeitos dos fármacos
18.
Int J Mol Med ; 35(6): 1773-8, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25847529

RESUMO

Regucalcin plays a pivotal role as a suppressor protein in signal transduction in various types of cells and tissues. The regucalcin gene is localized on the X chromosome. and its expression has been shown to be suppressed in various types of tumor tissue in animal and human subjects, suggesting a potential role of regucalcin in carcinogenesis. This study was undertaken to determine the effects of exogenous regucalcin on the proliferation of cloned human pancreatic cancer MIA PaCa-2 cells in vitro. The proliferation of the MIA PaCa-2 cells was suppressed following culture with regucalcin (0.01-10 nM). Such an effect was also observed in pancreatic cancer Pt45P1 cells, that highly expressed tissue factor (high TF), or Pt45P1 cells, that highly expressed alternativly spliced variants of tissue factor (asTF). In the MIA PaCa-2 cells, the suppressive effects of regucalcin on cell proliferation were not enhanced either in the presence of tumor necrosis factor-α (TNF-α), or in the presence of Bay K 8644, PD98059, staurosporine, wortmannin or 5,6-dichloro-1-ß-D-ribofuranosylbenzimidazole (DRB). However, this was not the case for gemcitabine, which was shown to suppress cell proliferation. Exogenous regucalcin did not cause apoptotic cell death in the MIA PaCa-2 cells in vitro. These findings demonstrate that exogenous regucalcin exerts suppressive effects on the proliferation of human pancreatic MIA PaCa-2 cells and that these effects are mediated through the inhibition of various signaling pathways related to nuclear factor-κB (NF-κB), extracellular signal-regulated kinase (ERK), protein kinase C, calcium signaling, phosphatidylinositol 3-kinase (PI3K) or nuclear transcription activity in vitro. Our data suggest that exogenous regucalcin exerts suppressive effects on the proliferation of human pancreatic cancer cells.


Assuntos
Proteínas de Ligação ao Cálcio/farmacologia , Proliferação de Células/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Peptídeos e Proteínas de Sinalização Intracelular/farmacologia , Proteínas de Neoplasias/biossíntese , Neoplasias Pancreáticas/metabolismo , Linhagem Celular Tumoral , Humanos , Neoplasias Pancreáticas/patologia
19.
Int J Mol Med ; 34(4): 1141-6, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-25050833

RESUMO

Regucalcin plays a pivotal role as a suppressor protein in signal transduction in various cell types. The regucalcin gene, which is localized on the X chromosome, consists of 7 exons and 6 introns. Decreased liver regucalcin gene expression has been suggested to play a suppressive role in the development of hepatocellular carcinogenesis in animal models. This study was undertaken to determine the changes in regucalcin gene expression in various human normal and tumor tissues, including liver, kidney, brain and lung tissues. The full-length and alternatively spliced variants of regucalcin mRNA were found to be expressed in various human tissues. This expression was suppressed in tumor tissues of hepatocellular carcinoma, kidney transitional cell carcinoma, brain malignant meningioma and lung non-small cell carcinoma. The full-length regucalcin protein was found to be highly expressed in normal human liver and kidney tissues; its expression was suppressed, however, in the liver and kidney tumor tissues. The spliced variant proteins were found to be expressed in the normal liver and kidney tissues, and decreased in the tumor tissues. Such alternative variants were not observed in the liver and kidneys of rats and mice. The alternatively spliced variants of the regucalcin gene were found to be expressed in various human normal and tumor tissues.


Assuntos
Processamento Alternativo/genética , Proteínas de Ligação ao Cálcio/genética , Peptídeos e Proteínas de Sinalização Intracelular/genética , Neoplasias/genética , Animais , Proteínas de Ligação ao Cálcio/metabolismo , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Camundongos , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos
20.
J Nat Med ; 68(3): 636-42, 2014 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-24756815

RESUMO

A novel isoflavone, erythgianin A (1), along with nine known compounds 2-10, was isolated from the stem bark of Erythrina poeppigiana (Leguminosae). The unusual isoflavone structure of 1, possessing a highly oxidized 3″,4″-dihydroxy-2″-hydroxymethyl-2″-methyl-2″,3″-dihydropyrano substituent, was determined on the basis of spectroscopic analyses. All of the isolated compounds were evaluated for their in vitro inhibitory activity toward human glyoxalase I. Among the isolates, isolupalbigenin (10) with two prenyl groups showed the highest inhibitory activity.


Assuntos
Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Erythrina/química , Lactoilglutationa Liase/antagonistas & inibidores , Fenóis/química , Fenóis/farmacologia , Humanos , Isoflavonas/química , Isoflavonas/farmacologia , Casca de Planta/química
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