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1.
Cancer Res ; 73(11): 3297-305, 2013 Jun 01.
Artículo en Inglés | MEDLINE | ID: mdl-23536554

RESUMEN

Despite the progress made in the early detection and treatment of prostate adenocarcinoma, the metastatic lesions from this tumor are incurable. We used genome-wide expression analysis of human prostate cancer cells with different metastatic behavior in animal models to reveal that bone-tropic phenotypes upregulate three genes encoding for the cytokine interleukin-1ß (IL-1ß), the chemokine CXCL6 (GCP-2), and the protease inhibitor elafin (PI3). The Oncomine database revealed that these three genes are significantly upregulated in human prostate cancer versus normal tissue and correlate with Gleason scores ≥7. This correlation was further validated for IL-1ß by immunodetection in prostate tissue arrays. Our study also shows that the exogenous overexpression of IL-1ß in nonmetastatic cancer cells promotes their growth into large skeletal lesions in mice, whereas its knockdown significantly impairs the bone progression of highly metastatic cells. In addition, IL-1ß secreted by metastatic cells induced the overexpression of COX-2 (PTGS2) in human bone mesenchymal cells treated with conditioned media from bone metastatic prostate cancer cells. Finally, we inspected human tissue specimens from skeletal metastases and detected prostate cancer cells positive for both IL-1ß and synaptophysin while concurrently lacking prostate-specific antigen (PSA, KLK3) expression. Collectively, these findings indicate that IL-1ß supports the skeletal colonization and metastatic progression of prostate cancer cells with an acquired neuroendocrine phenotype.


Asunto(s)
Neoplasias Óseas/secundario , Carcinoma Neuroendocrino/patología , Interleucina-1beta/biosíntesis , Neoplasias de la Próstata/patología , Adenocarcinoma/genética , Adenocarcinoma/metabolismo , Adenocarcinoma/patología , Animales , Neoplasias Óseas/genética , Neoplasias Óseas/metabolismo , Carcinoma Neuroendocrino/genética , Carcinoma Neuroendocrino/metabolismo , Línea Celular Tumoral , Progresión de la Enfermedad , Regulación Neoplásica de la Expresión Génica , Xenoinjertos , Humanos , Huésped Inmunocomprometido , Interleucina-1beta/genética , Masculino , Ratones , Células 3T3 NIH , Células Neuroendocrinas/metabolismo , Células Neuroendocrinas/patología , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/metabolismo , Receptor alfa de Factor de Crecimiento Derivado de Plaquetas/genética , Receptor alfa de Factor de Crecimiento Derivado de Plaquetas/metabolismo , Sinaptofisina/biosíntesis , Regulación hacia Arriba
2.
J Biol Chem ; 287(14): 11070-81, 2012 Mar 30.
Artículo en Inglés | MEDLINE | ID: mdl-22275356

RESUMEN

Cancer cells universally increase glucose and glutamine consumption, leading to the altered metabolic state known as the Warburg effect; one metabolic pathway, highly dependent on glucose and glutamine, is the hexosamine biosynthetic pathway. Increased flux through the hexosamine biosynthetic pathway leads to increases in the post-translational addition of O-linked ß-N-acetylglucosamine (O-GlcNAc) to various nuclear and cytosolic proteins. A number of these target proteins are implicated in cancer, and recently, O-GlcNAcylation was shown to play a role in breast cancer; however, O-GlcNAcylation in other cancers remains poorly defined. Here, we show that O-GlcNAc transferase (OGT) is overexpressed in prostate cancer compared with normal prostate epithelium and that OGT protein and O-GlcNAc levels are elevated in prostate carcinoma cell lines. Reducing O-GlcNAcylation in PC3-ML cells was associated with reduced expression of matrix metalloproteinase (MMP)-2, MMP-9, and VEGF, resulting in inhibition of invasion and angiogenesis. OGT-mediated regulation of invasion and angiogenesis was dependent upon regulation of the oncogenic transcription factor FoxM1, a key regulator of invasion and angiogenesis, as reducing OGT expression led to increased FoxM1 protein degradation. Conversely, overexpression of a degradation-resistant FoxM1 mutant abrogated OGT RNAi-mediated effects on invasion, MMP levels, angiogenesis, and VEGF expression. Using a mouse model of metastasis, we found that reduction of OGT expression blocked bone metastasis. Altogether, these data suggest that as prostate cancer cells alter glucose and glutamine levels, O-GlcNAc modifications and OGT levels become elevated and are required for regulation of malignant properties, implicating OGT as a novel therapeutic target in the treatment of cancer.


Asunto(s)
N-Acetilglucosaminiltransferasas/metabolismo , Neovascularización Patológica/enzimología , Neoplasias de la Próstata/irrigación sanguínea , Neoplasias de la Próstata/patología , Acetilglucosamina/metabolismo , Animales , Neoplasias Óseas/prevención & control , Neoplasias Óseas/secundario , Línea Celular Tumoral , Proliferación Celular , Transformación Celular Neoplásica , Inhibidor p27 de las Quinasas Dependientes de la Ciclina/genética , Proteína Forkhead Box M1 , Factores de Transcripción Forkhead/genética , Factores de Transcripción Forkhead/metabolismo , Regulación Neoplásica de la Expresión Génica , Masculino , Metaloproteinasa 2 de la Matriz/genética , Metaloproteinasa 9 de la Matriz/genética , Ratones , Mutación , N-Acetilglucosaminiltransferasas/deficiencia , N-Acetilglucosaminiltransferasas/genética , Invasividad Neoplásica , Metástasis de la Neoplasia , Neoplasias de la Próstata/enzimología , Neoplasias de la Próstata/genética , Proteolisis , Interferencia de ARN , Factor A de Crecimiento Endotelial Vascular/genética
3.
Mol Biol Cell ; 21(22): 3829-37, 2010 Nov 15.
Artículo en Inglés | MEDLINE | ID: mdl-20861305

RESUMEN

Proper adhesion to extracellular matrix is critical for epithelial cell survival. Detachment from matrix signals results in apoptosis, referred to as anoikis. Selective apoptosis of cells that become detached from matrix is associated with the formation of a lumen in three-dimensional mammary epithelial acinar structures in vitro. Because early breast cancer lesions such as carcinoma in situ, characterized by ducts exhibiting lumens filled with cells, are often associated with hypoxic markers, we sought to examine the role of hypoxia in anoikis and lumen formation in mammary epithelial cells. Here, we show that hypoxic conditions inhibit anoikis and block expression of proapoptotic BH3-only family members Bim and Bmf in epithelial cells. Hypoxia-mediated anoikis protection is associated with increased activation of the epidermal growth factor receptor-mitogen-activated protein kinase kinase-extracellular signal-regulated kinase (Erk) kinase pathway and requires the hypoxia-activated transcription factor. Consistent with these data, hypoxic conditions inhibit luminal clearing during morphogenesis in human mammary epithelial acini when grown in three-dimensional cultures and are associated with decreased expression of Bim and Bmf as well as Erk activation. We show that hypoxia regulates specific cell survival pathways that disrupt tissue architecture related to clearing of luminal space during mammary morphogenesis and suggest that hypoxia-mediated anoikis resistance may contribute to cancer progression.


Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/metabolismo , Anoicis , Proteínas Reguladoras de la Apoptosis/metabolismo , Células Epiteliales/metabolismo , Proteínas de la Membrana/metabolismo , Proteínas Proto-Oncogénicas/metabolismo , Proteínas Adaptadoras Transductoras de Señales/genética , Proteínas Reguladoras de la Apoptosis/genética , Proteína 11 Similar a Bcl2 , Butadienos/farmacología , Técnicas de Cultivo de Célula , Hipoxia de la Célula , Línea Celular , Línea Celular Tumoral , Activación Enzimática/efectos de los fármacos , Inhibidores Enzimáticos/farmacología , Células Epiteliales/citología , Quinasas MAP Reguladas por Señal Extracelular/antagonistas & inhibidores , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Expresión Génica , Humanos , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Immunoblotting , MAP Quinasa Quinasa 1/antagonistas & inhibidores , MAP Quinasa Quinasa 1/metabolismo , Glándulas Mamarias Humanas/citología , Glándulas Mamarias Humanas/crecimiento & desarrollo , Glándulas Mamarias Humanas/metabolismo , Proteínas de la Membrana/genética , Proteínas Quinasas Activadas por Mitógenos/antagonistas & inhibidores , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Morfogénesis , Nitrilos/farmacología , Proteínas Proto-Oncogénicas/genética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa
4.
J Cell Sci ; 123(Pt 8): 1373-82, 2010 Apr 15.
Artículo en Inglés | MEDLINE | ID: mdl-20332114

RESUMEN

ErbB2, a receptor tyrosine kinase highly expressed in many tumors, is known to inhibit apoptotic signals. Overexpression of ErbB2 causes anoikis resistance that contributes to luminal filling in three-dimensional mammary epithelial acinar structures in vitro. Given that integrins and growth factor receptors are highly interdependent for function, we examined the role of integrin subunits in ErbB2-mediated survival signaling. Here, we show that MCF-10A cells overexpressing ErbB2 upregulate integrin alpha5 via the MAP-kinase pathway in three-dimensional acini and found elevated integrin alpha5 levels associated with ErbB2 status in human breast cancer. Integrin alpha5 is required for ErbB2-mediated anoikis resistance and for optimal ErbB2 signaling to the Mek-Erk-Bim axis as depletion of integrin alpha5 reverses anoikis resistance and Bim inhibition. Integrin alpha5 is required for full activation of ErbB2 tyrosine phosphorylation on Y877 and ErbB2 phosphorylation is associated with increased activity of Src in the absence of adhesion. Indeed, we show that blocking elevated Src activity during cell detachment reverses ErbB2-mediated survival and Bim repression. Thus, integrin alpha5 serves as a key mediator of Src and ErbB2-survival signaling in low adhesion states, which are necessary to block the pro-anoikis mediator Bim, and we suggest that this pathway represents a potential novel therapeutic target in ErbB2-positive tumors.


Asunto(s)
Anoicis , Células Epiteliales/enzimología , Integrina alfa5/metabolismo , Glándulas Mamarias Humanas/citología , Receptor ErbB-2/metabolismo , Familia-src Quinasas/metabolismo , Proteínas Reguladoras de la Apoptosis/metabolismo , Proteína 11 Similar a Bcl2 , Neoplasias de la Mama/enzimología , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Adhesión Celular , Supervivencia Celular , Activación Enzimática , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Integrina alfa5/genética , Sistema de Señalización de MAP Quinasas , Glándulas Mamarias Humanas/crecimiento & desarrollo , Proteínas de la Membrana/metabolismo , Quinasas de Proteína Quinasa Activadas por Mitógenos/metabolismo , Morfogénesis , Proteínas Proto-Oncogénicas/metabolismo , Regulación hacia Arriba/genética
5.
Genes Dev ; 22(7): 884-93, 2008 Apr 01.
Artículo en Inglés | MEDLINE | ID: mdl-18334619

RESUMEN

VHL, NF-1, c-Ret, and Succinate Dehydrogenase Subunits B and D act on a developmental apoptotic pathway that is activated when nerve growth factor (NGF) becomes limiting for neuronal progenitor cells and requires the EglN3 prolyl hydroxylase as a downstream effector. Germline mutations of these genes cause familial pheochromocytoma and other neural crest-derived tumors. Using an unbiased shRNA screen we found that the kinesin KIF1Bbeta acts downstream from EglN3 and is both necessary and sufficient for neuronal apoptosis when NGF becomes limiting. KIF1Bbeta maps to chromosome 1p36.2, which is frequently deleted in neural crest-derived tumors including neuroblastomas. We identified inherited loss-of-function KIF1Bbeta missense mutations in neuroblastomas and pheochromocytomas and an acquired loss-of-function mutation in a medulloblastoma, arguing that KIF1Bbeta is a pathogenic target of these deletions.


Asunto(s)
Apoptosis , Cromosomas de los Mamíferos/genética , Proteínas de Unión al ADN/metabolismo , Proteínas Inmediatas-Precoces/metabolismo , Cinesinas/metabolismo , Proteínas del Tejido Nervioso/metabolismo , Proteínas Supresoras de Tumor/metabolismo , Animales , Animales Recién Nacidos , Células Cultivadas , Niño , Mapeo Cromosómico , Proteínas de Unión al ADN/genética , Células HeLa , Humanos , Prolina Dioxigenasas del Factor Inducible por Hipoxia , Proteínas Inmediatas-Precoces/genética , Immunoblotting , Cinesinas/genética , Meduloblastoma/genética , Meduloblastoma/patología , Ratones , Ratones Noqueados , Modelos Biológicos , Mutación Missense , Proteínas del Tejido Nervioso/genética , Neuroblastoma/genética , Neuroblastoma/patología , Neuronas/citología , Neuronas/metabolismo , Células PC12 , Feocromocitoma/genética , Feocromocitoma/patología , Procolágeno-Prolina Dioxigenasa , Interferencia de ARN , Ratas , Proteínas Supresoras de Tumor/genética
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