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1.
Nat Med ; 12(8): 933-8, 2006 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-16862154

RESUMO

CD82, also known as KAI1, was recently identified as a prostate cancer metastasis suppressor gene on human chromosome 11p1.2 (ref. 1). The product of CD82 is KAI1, a 40- to 75-kDa tetraspanin cell-surface protein also known as the leukocyte cell-surface marker CD82 (refs. 1,2). Downregulation of KAI1 has been found to be clinically associated with metastatic progression in a variety of cancers, whereas overexpression of CD82 specifically suppresses tumor metastasis in various animal models. To define the mechanism of action of KAI1, we used a yeast two-hybrid screen and identified an endothelial cell-surface protein, DARC (also known as gp-Fy), as an interacting partner of KAI1. Our results indicate that the cancer cells expressing KAI1 attach to vascular endothelial cells through direct interaction between KAI1 and DARC, and that this interaction leads to inhibition of tumor cell proliferation and induction of senescence by modulating the expression of TBX2 and p21. Furthermore, the metastasis-suppression activity of KAI1 was significantly compromised in DARC knockout mice, whereas KAI1 completely abrogated pulmonary metastasis in wild-type and heterozygous littermates. These results provide direct evidence that DARC is essential for the function of CD82 as a suppressor of metastasis.


Assuntos
Sistema do Grupo Sanguíneo Duffy/metabolismo , Endotélio Vascular/metabolismo , Proteína Kangai-1/metabolismo , Neoplasias Pulmonares/patologia , Glicoproteínas de Membrana/metabolismo , Metástase Neoplásica/prevenção & controle , Receptores de Superfície Celular/metabolismo , Alelos , Sequência de Aminoácidos , Animais , Sequência de Bases , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Senescência Celular/fisiologia , Inibidor de Quinase Dependente de Ciclina p21/metabolismo , Sistema do Grupo Sanguíneo Duffy/química , Feminino , Heterozigoto , Humanos , Proteína Kangai-1/química , Masculino , Glicoproteínas de Membrana/química , Glicoproteínas de Membrana/genética , Camundongos , Camundongos Knockout , Dados de Sequência Molecular , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Estrutura Terciária de Proteína , Ratos , Receptores de Superfície Celular/química , Proteínas com Domínio T/metabolismo
2.
Cancer Res ; 66(24): 11983-90, 2006 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-17178897

RESUMO

The tumor metastasis suppressor gene Drg-1 has been shown to suppress metastasis without affecting tumorigenicity in immunodeficient mouse models of prostate and colon cancer. Expression of Drg-1 has also been found to have a significant inverse correlation with metastasis or invasiveness in various types of human cancer. However, how Drg-1 exerts its metastasis suppressor function remains unknown. In the present study, to elucidate the mechanism of action of the Drg-1 gene, we did a microarray analysis and found that induction of Drg-1 significantly inhibited the expression of activating transcription factor (ATF) 3, a member of the ATF/cyclic AMP-responsive element binding protein family of transcription factors. We also showed that Drg-1 attenuated the endogenous level of ATF3 mRNA and protein in prostate cancer cells, whereas Drg-1 small interfering RNA up-regulated the ATF3 expression. Furthermore, Drg-1 suppressed the promoter activity of the ATF3 gene, indicating that Drg-1 regulates ATF3 expression at the transcriptional level. Our immunohistochemical analysis on prostate cancer specimens revealed that nuclear expression of ATF3 was inversely correlated to Drg-1 expression and positively correlated to metastases. Consistently, we have found that ATF3 overexpression promoted invasiveness of prostate tumor cells in vitro, whereas Drg-1 suppressed the invasive ability of these cells. More importantly, overexpression of ATF3 in prostate cancer cells significantly enhanced spontaneous lung metastasis of these cells without affecting primary tumorigenicity in a severe combined immunodeficient mouse model. Taken together, our results strongly suggest that Drg-1 suppresses metastasis of prostate tumor cells, at least in part, by inhibiting the invasive ability of the cells via down-regulation of the expression of the ATF3 gene.


Assuntos
Fator 3 Ativador da Transcrição/genética , Proteínas de Ligação ao GTP/genética , Regulação Neoplásica da Expressão Gênica , Neoplasias da Próstata/genética , Linhagem Celular Tumoral , Humanos , Masculino , Metástase Neoplásica/genética , Metástase Neoplásica/prevenção & controle , Plasmídeos , Neoplasias da Próstata/patologia , Mapeamento por Restrição , Transfecção
3.
Oncogene ; 24(34): 5389-95, 2005 Aug 11.
Artigo em Inglês | MEDLINE | ID: mdl-15897909

RESUMO

Fatty acid synthase (FAS), a key enzyme of the fatty acid biosynthetic pathway, has been shown to be overexpressed in various types of human cancer and is, therefore, considered to be an attractive target for anticancer therapy. However, the exact mechanism of overexpression of the FAS gene in tumor cells is not well understood. In this report, we demonstrate that the expression of the tumor suppressor gene PTEN has a significant inverse correlation with FAS expression in the case of prostate cancer in the clinical setting, and inhibition of the PTEN gene leads to the overexpression of FAS in vitro. We also found that the combination of the expression status of these two genes is a better prognostic marker than either gene alone. Furthermore, our results indicate that the specific inhibition of FAS gene by siRNA leads to apoptosis of prostate tumor cells, and inhibition of PI 3-kinase pathway synergizes with FAS siRNA to enhance tumor cell death. These results provide a strong rationale for exploring the therapeutic use of an inhibitor of the PTEN signaling pathway in conjunction with the FAS siRNA to inhibit prostate tumor growth.


Assuntos
Apoptose , Ácido Graxo Sintases/metabolismo , Regulação Neoplásica da Expressão Gênica , Fosfatidilinositol 3-Quinases/metabolismo , Monoéster Fosfórico Hidrolases/biossíntese , Neoplasias da Próstata/genética , Proteínas Supressoras de Tumor/biossíntese , Idoso , Idoso de 80 Anos ou mais , Ácido Graxo Sintases/biossíntese , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , PTEN Fosfo-Hidrolase , Prognóstico , Neoplasias da Próstata/patologia , Interferência de RNA , Transdução de Sinais , Análise de Sobrevida
4.
Cancer Res ; 64(21): 7655-60, 2004 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-15520163

RESUMO

PTEN (phosphatase and tensin homologue deleted on chromosome 10) has been shown to be inactivated in a wide variety of cancers, and the role of this gene as a tumor suppressor has been well established. On the other hand, results of recent animal studies as well as clinical evidence indicate that PTEN is also involved in tumor metastasis suppression. Although PTEN is known to play a key role in controlling cell growth and apoptosis, how PTEN exerts the metastasis suppressor function remains largely unknown. Recently, a microarray analysis identified the Drg-1 gene (differentiation related gene 1) as one of the potential targets of PTEN. The Drg-1 gene has been shown to suppress tumor metastasis in animal models of prostate and colon cancer, and the expression of this gene is significantly reduced with advancement of prostate and breast cancers in clinical setting. In this study, we explored the possibility that PTEN controls tumor metastasis by regulating the expression of the Drg-1 gene. Our results indicate that overexpression of PTEN significantly augments the endogenous expression of Drg-1 protein, whereas inhibition of PTEN by small interfering RNA decreases Drg-1 in a dose- and time-dependent manner. We also found that the control of the Drg-1 gene by PTEN seems to be at the transcriptional level, and that a phospho-Akt inhibitor restores the Drg-1 expression, indicating that PTEN controls Drg-1 by an Akt-dependent pathway. Consistent with these results, our immunohistochemical analysis revealed that PTEN expression correlates significantly with Drg-1 in both prostate and breast cancer cases. Furthermore, combination of the two markers, PTEN and Drg-1, emerged as a significantly better predictor of prostate and breast cancer patient survival than either marker alone.


Assuntos
Neoplasias da Mama/genética , Proteínas de Ciclo Celular/genética , Genes Supressores de Tumor , Monoéster Fosfórico Hidrolases/fisiologia , Neoplasias da Próstata/genética , Proteínas Supressoras de Tumor/fisiologia , Neoplasias da Mama/mortalidade , Linhagem Celular Tumoral , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Peptídeos e Proteínas de Sinalização Intracelular , Masculino , PTEN Fosfo-Hidrolase , Neoplasias da Próstata/mortalidade , Taxa de Sobrevida , Regulação para Cima
5.
Cancer Res ; 68(18): 7613-20, 2008 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-18794150

RESUMO

RhoC is a member of the Ras-homologous family of genes which have been implicated in tumorigenesis and tumor progression. However, the exact role of RhoC is controversial and is yet to be clarified. We have examined the effect of RhoC on prostate tumor cells and found that RhoC had no effect on cell proliferation in vitro or on tumor growth in mice. However, RhoC significantly enhanced the metastatic ability of the tumor cells in these animals, suggesting that RhoC affects only the metastasis but not the growth of prostate tumor cells. The results of our immunohistochemical analyses on tumor specimens from 63 patients with prostate cancer indicate that RhoC expression had no significant correlation with Gleason grade. However, the expression of RhoC showed significant positive correlation with both lymph node and distant metastasis, and it was inversely correlated with patient survival. We also found that RhoC significantly augmented the invasion and motility of prostate tumor cells by activating matrix metalloproteinases 2 and 9 (MMP2 and MMP9) in vitro. The results of our antibody array analysis for signal molecules revealed that RhoC significantly activated kinases including mitogen-activated protein kinase (MAPK), focal adhesion kinase (FAK), Akt, and Pyk2. Inhibition of Pyk2 kinase blocked the RhoC-dependent activation of FAK, MAPK, and Akt, followed by the suppression of MMP2 and MMP9. Inhibitors of both MAPK and Akt also significantly blocked the activities of these MMPs. Therefore, our results indicate that RhoC promotes tumor metastasis in prostate cancer by sequential activation of Pyk2, FAK, MAPK, and Akt followed by the up-regulation of MMP2 and MMP9, which results in the stimulation of invasiveness of tumor cells.


Assuntos
Quinase 2 de Adesão Focal/metabolismo , Neoplasias da Próstata/metabolismo , Proteínas rho de Ligação ao GTP/metabolismo , Animais , Processos de Crescimento Celular/fisiologia , Linhagem Celular Tumoral , Movimento Celular/fisiologia , Ativação Enzimática , Quinase 1 de Adesão Focal/metabolismo , Humanos , Masculino , Metaloproteinase 2 da Matriz/biossíntese , Metaloproteinase 2 da Matriz/genética , Metaloproteinase 9 da Matriz/biossíntese , Metaloproteinase 9 da Matriz/genética , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Metástase Neoplásica , Neoplasias da Próstata/enzimologia , Neoplasias da Próstata/genética , Neoplasias da Próstata/patologia , Ratos , Transdução de Sinais , Regulação para Cima , Proteínas rho de Ligação ao GTP/biossíntese , Proteína de Ligação a GTP rhoC
6.
Cancer Res ; 68(4): 1003-11, 2008 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-18281474

RESUMO

The fatty acid synthase (FAS) gene is significantly up-regulated in various types of cancers, and blocking the FAS expression results in apoptosis of tumor cells. Therefore, FAS is considered to be an attractive target for anticancer therapy. However, the molecular mechanism by which the FAS gene is up-regulated in tumor cells is poorly understood. We found that FAS was significantly up-regulated by hypoxia, which was also accompanied by reactive oxygen species (ROS) generation in human breast cancer cell lines. The FAS expression was also activated by H(2)O(2), whereas N-acetyl-L-cystein, a ROS inhibitor, suppressed the expression. We also found that the hypoxia significantly up-regulated sterol regulatory-element binding protein (SREBP)-1, the major transcriptional regulator of the FAS gene, via phosphorylation of Akt followed by activation of hypoxia-inducible factor 1 (HIF1). Moreover, our results of reporter assay and chromatin immunoprecipitation analysis indicate that SREBP-1 strongly bound to the SREBP binding site/E-box sequence on the FAS promoter under hypoxia. In our xenograft mouse model, FAS was strongly expressed in the hypoxic regions of the tumor. In addition, our results of immunohistochemical analysis for human breast tumor specimens indicate that the expressions of both FAS and SREBP-1 were colocalized with hypoxic regions in the tumors. Furthermore, we found that hypoxia-induced chemoresistance to cyclophosphamide was partially blocked by a combination of FAS inhibitor and cyclophosphamide. Taken together, our results indicate that FAS gene is up-regulated by hypoxia via activation of the Akt and HIF1 followed by the induction of the SREBP-1 gene, and that hypoxia-induced chemoresistance is partly due to the up-regulation of FAS.


Assuntos
Neoplasias da Mama/enzimologia , Neoplasias da Mama/genética , Ácido Graxo Sintases/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Hipóxia Celular/genética , Linhagem Celular Tumoral , Ciclofosfamida/administração & dosagem , Ciclofosfamida/farmacologia , Resistencia a Medicamentos Antineoplásicos , Ativação Enzimática , Inibidores Enzimáticos/administração & dosagem , Ácido Graxo Sintases/antagonistas & inibidores , Ácido Graxo Sintases/biossíntese , Feminino , Regulação Enzimológica da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Fator 1 Induzível por Hipóxia/biossíntese , Fator 1 Induzível por Hipóxia/genética , Camundongos , Camundongos Nus , Espécies Reativas de Oxigênio/metabolismo , Regulação para Cima
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