Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 4 de 4
Filtrar
Más filtros

Banco de datos
Tipo del documento
País de afiliación
Intervalo de año de publicación
1.
Cancer Res ; 81(19): 4981-4993, 2021 10 01.
Artículo en Inglés | MEDLINE | ID: mdl-34362796

RESUMEN

Dysregulated lipid metabolism is a prominent feature of prostate cancer that is driven by androgen receptor (AR) signaling. Here we used quantitative mass spectrometry to define the "lipidome" in prostate tumors with matched benign tissues (n = 21), independent unmatched tissues (n = 47), and primary prostate explants cultured with the clinical AR antagonist enzalutamide (n = 43). Significant differences in lipid composition were detected and spatially visualized in tumors compared with matched benign samples. Notably, tumors featured higher proportions of monounsaturated lipids overall and elongated fatty acid chains in phosphatidylinositol and phosphatidylserine lipids. Significant associations between lipid profile and malignancy were validated in unmatched samples, and phospholipid composition was characteristically altered in patient tissues that responded to AR inhibition. Importantly, targeting tumor-related lipid features via inhibition of acetyl-CoA carboxylase 1 significantly reduced cellular proliferation and induced apoptosis in tissue explants. This characterization of the prostate cancer lipidome in clinical tissues reveals enhanced fatty acid synthesis, elongation, and desaturation as tumor-defining features, with potential for therapeutic targeting. SIGNIFICANCE: This study identifies malignancy and treatment-associated changes in lipid composition of clinical prostate cancer tissues, suggesting that mediators of these lipidomic changes could be targeted using existing metabolic agents.


Asunto(s)
Metabolismo de los Lípidos , Lipidómica , Lípidos de la Membrana/metabolismo , Neoplasias de la Próstata/metabolismo , Biomarcadores , Biología Computacional/métodos , Metabolismo Energético , Humanos , Metabolismo de los Lípidos/efectos de los fármacos , Lipidómica/métodos , Masculino , Metabolómica/métodos , Terapia Molecular Dirigida , Clasificación del Tumor , Estadificación de Neoplasias , Neoplasias de la Próstata/diagnóstico , Neoplasias de la Próstata/tratamiento farmacológico , Neoplasias de la Próstata/etiología , Espectrometría de Masa por Ionización de Electrospray , Espectrometría de Masa por Láser de Matriz Asistida de Ionización Desorción , Espectrometría de Masas en Tándem , Regulador Transcripcional ERG/genética , Regulador Transcripcional ERG/metabolismo
2.
Cancer Res ; 81(7): 1704-1718, 2021 04 01.
Artículo en Inglés | MEDLINE | ID: mdl-33547161

RESUMEN

The androgen receptor (AR) is the key oncogenic driver of prostate cancer, and despite implementation of novel AR targeting therapies, outcomes for metastatic disease remain dismal. There is an urgent need to better understand androgen-regulated cellular processes to more effectively target the AR dependence of prostate cancer cells through new therapeutic vulnerabilities. Transcriptomic studies have consistently identified lipid metabolism as a hallmark of enhanced AR signaling in prostate cancer, yet the relationship between AR and the lipidome remains undefined. Using mass spectrometry-based lipidomics, this study reveals increased fatty acyl chain length in phospholipids from prostate cancer cells and patient-derived explants as one of the most striking androgen-regulated changes to lipid metabolism. Potent and direct AR-mediated induction of ELOVL fatty acid elongase 5 (ELOVL5), an enzyme that catalyzes fatty acid elongation, was demonstrated in prostate cancer cells, xenografts, and clinical tumors. Assessment of mRNA and protein in large-scale data sets revealed ELOVL5 as the predominant ELOVL expressed and upregulated in prostate cancer compared with nonmalignant prostate. ELOVL5 depletion markedly altered mitochondrial morphology and function, leading to excess generation of reactive oxygen species and resulting in suppression of prostate cancer cell proliferation, 3D growth, and in vivo tumor growth and metastasis. Supplementation with the monounsaturated fatty acid cis-vaccenic acid, a direct product of ELOVL5 elongation, reversed the oxidative stress and associated cell proliferation and migration effects of ELOVL5 knockdown. Collectively, these results identify lipid elongation as a protumorigenic metabolic pathway in prostate cancer that is androgen-regulated, critical for metastasis, and targetable via ELOVL5. SIGNIFICANCE: This study identifies phospholipid elongation as a new metabolic target of androgen action that is critical for prostate tumor metastasis.


Asunto(s)
Elongasas de Ácidos Grasos/antagonistas & inhibidores , Neoplasias de la Próstata/tratamiento farmacológico , ARN Interferente Pequeño/uso terapéutico , Animales , Movimiento Celular/efectos de los fármacos , Movimiento Celular/genética , Proliferación Celular/efectos de los fármacos , Proliferación Celular/genética , Elongasas de Ácidos Grasos/genética , Elongasas de Ácidos Grasos/fisiología , Regulación Enzimológica de la Expresión Génica/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Técnicas de Silenciamiento del Gen , Humanos , Metabolismo de los Lípidos/genética , Masculino , Ratones , Ratones Endogámicos NOD , Ratones SCID , Terapia Molecular Dirigida/métodos , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/metabolismo , Neoplasias de la Próstata/patología , ARN Interferente Pequeño/farmacología , Receptores Androgénicos/fisiología , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de Xenoinjerto
3.
Oncotarget ; 7(11): 12582-97, 2016 Mar 15.
Artículo en Inglés | MEDLINE | ID: mdl-26862848

RESUMEN

Lung cancer is the leading cause of cancer death. Beyond first line treatment, few therapeutic options are available, particularly for squamous cell carcinoma (SCC). Here, we have explored the phospholipidomes of 30 human SCCs and found that they almost invariably (in 96.7% of cases) contain phospholipids with longer acyl chains compared to matched normal tissues. This trait was confirmed using in situ 2D-imaging MS on tissue sections and by phospholipidomics of tumor and normal lung tissue of the L-IkkαKA/KA mouse model of lung SCC. In both human and mouse, the increase in acyl chain length in cancer tissue was accompanied by significant changes in the expression of acyl chain elongases (ELOVLs). Functional screening of differentially expressed ELOVLs by selective gene knockdown in SCC cell lines followed by phospholipidomics revealed ELOVL6 as the main elongation enzyme responsible for acyl chain elongation in cancer cells. Interestingly, inhibition of ELOVL6 drastically reduced colony formation of multiple SCC cell lines in vitro and significantly attenuated their growth as xenografts in vivo in mouse models. These findings identify acyl chain elongation as one of the most common traits of lung SCC discovered so far and pinpoint ELOVL6 as a novel potential target for cancer intervention.


Asunto(s)
Acetiltransferasas/metabolismo , Carcinoma de Células Escamosas , Neoplasias Pulmonares , Fosfolípidos/química , Animales , Carcinoma de Células Escamosas/química , Elongasas de Ácidos Grasos , Xenoinjertos , Humanos , Neoplasias Pulmonares/química , Ratones
4.
Cancer Res ; 70(20): 8117-26, 2010 Oct 15.
Artículo en Inglés | MEDLINE | ID: mdl-20876798

RESUMEN

Activation of de novo lipogenesis in cancer cells is increasingly recognized as a hallmark of aggressive cancers and has been implicated in the production of membranes for rapid cell proliferation. In the current report, we provide evidence that this activation has a more profound role. Using a mass spectrometry-based phospholipid analysis approach, we show that clinical tumor tissues that display the lipogenic phenotype show an increase in the degree of lipid saturation compared with nonlipogenic tumors. Reversal of the lipogenic switch in cancer cells by treatment with the lipogenesis inhibitor soraphen A or by targeting lipogenic enzymes with small interfering RNA leads to a marked decrease in saturated and mono-unsaturated phospholipid species and increases the relative degree of polyunsaturation. Because polyunsaturated acyl chains are more susceptible to peroxidation, inhibition of lipogenesis increases the levels of peroxidation end products and renders cells more susceptible to oxidative stress-induced cell death. As saturated lipids pack more densely, modulation of lipogenesis also alters lateral and transversal membrane dynamics as revealed by diffusion of membrane-targeted green fluorescent protein and by the uptake and response to doxorubicin. These data show that shifting lipid acquisition from lipid uptake toward de novo lipogenesis dramatically changes membrane properties and protects cells from both endogenous and exogenous insults. These findings provide important new insights into the role of de novo lipogenesis in cancer cells, and they provide a rationale for the use of lipogenesis inhibitors as antineoplastic agents and as chemotherapeutic sensitizers.


Asunto(s)
Radicales Libres/farmacología , Lipogénesis/fisiología , Lípidos de la Membrana/metabolismo , Neoplasias/metabolismo , Antibióticos Antineoplásicos/metabolismo , División Celular , Membrana Celular/efectos de los fármacos , Membrana Celular/fisiología , Colesterol/metabolismo , Doxorrubicina/metabolismo , Células HCT116/efectos de los fármacos , Células HCT116/metabolismo , Humanos , Immunoblotting , Peroxidación de Lípido , Masculino , Neoplasias/patología , Fosfolípidos/metabolismo , Próstata/metabolismo , Próstata/patología , Prostatectomía , Neoplasias de la Próstata/metabolismo , Neoplasias de la Próstata/patología , ARN Interferente Pequeño/genética , Espectrometría de Masa por Ionización de Electrospray , Transfección , Triglicéridos/metabolismo
SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA