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1.
Oncotarget ; 7(34): 54852-54866, 2016 Aug 23.
Artículo en Inglés | MEDLINE | ID: mdl-27363026

RESUMEN

Exosomes, a subgroup of extracellular vesicles (EVs), have been shown to serve as a conduit for the exchange of genetic information between cells. Exosomes are released from all types of cells but in abundance from cancer cells. The contents of exosomes consist of proteins and genetic material (mRNA, DNA and miRNA) from the cell of origin. In this study, we examined the effects of exosomes derived from human lung cancer serum and both highly metastatic and non-metastatic cells on recipient human bronchial epithelial cells (HBECs). We found that exosomes derived from highly metastatic lung cancer cells and human late stage lung cancer serum induced vimentin expression, and epithelial to mesenchymal transition (EMT) in HBECs. Exosomes derived from highly metastatic cancer cells as well as late stage lung cancer serum induce migration, invasion and proliferation in non-cancerous recipient cells. Our results suggest that cancer derived exosomes could be a potential mediator of EMT in the recipient cells.


Asunto(s)
Células Epiteliales/metabolismo , Transición Epitelial-Mesenquimal/genética , Exosomas/genética , Neoplasias Pulmonares/genética , Adulto , Anciano , Línea Celular , Línea Celular Tumoral , Células Epiteliales/patología , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Masculino , Persona de Mediana Edad , Interferencia de ARN , Vimentina/genética , Vimentina/metabolismo
2.
Food Chem Toxicol ; 98(Pt A): 66-72, 2016 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-27311798

RESUMEN

Cancer is the leading cause of death worldwide. Despite significant progress in the field leading to identification of molecular signatures of individual tumors and the development of targeted therapies, early cancer diagnosis remains a clinical challenge. The emerging era of personalized medicine has intensified research towards biomarkers that can be obtained via noninvasive means. The recent discovery of extracellular vesicles (EVs), nano-vesicles secreted by the cell, in circulation has stimulated interest in their clinical utility as cancer biomarkers. EVs are secreted from all types of cells and their contents reflect the physiological and pathological state of the cell. Multiple clinical trials are underway investigating the clinical potential of EV content to serve as biomarkers and therapeutics. However, much work remains to translate EV content into clinical application.


Asunto(s)
Biomarcadores de Tumor/genética , Vesículas Extracelulares/patología , MicroARNs/genética , Neoplasias/diagnóstico , Animales , Vesículas Extracelulares/genética , Humanos , Neoplasias/genética
3.
Respir Med ; 109(7): 803-12, 2015 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-25910758

RESUMEN

Lung cancer is the number one cause of cancer related deaths. The lack of specific and accurate tools for early diagnosis and minimal targeted therapeutics both contribute to poor outcomes. The recent discovery of microRNAs (miRNAs) revealed a novel mechanism for post-transcriptional regulation in cancer and has created new opportunities for the development of diagnostics, prognostics and targeted therapeutics. In lung cancer, miRNA expression profiles distinguish histological subtypes, predict chemotherapeutic response and are associated with prognosis, metastasis and survival. Furthermore, miRNAs circulate in body fluids and hence may serve as important biomarkers for early diagnosis or stratify patients for personalized therapeutic strategies. Here, we provide an overview of the miRNAs implicated in lung cancer, with an emphasis on their clinical utility.


Asunto(s)
Biomarcadores de Tumor/genética , Regulación Neoplásica de la Expresión Génica , Terapia Genética/métodos , Neoplasias Pulmonares , MicroARNs/genética , Biomarcadores de Tumor/biosíntesis , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/terapia , MicroARNs/biosíntesis , Pronóstico
4.
Cell ; 152(3): 599-611, 2013 Jan 31.
Artículo en Inglés | MEDLINE | ID: mdl-23374352

RESUMEN

Tumor cells have high-energetic and anabolic needs and are known to adapt their metabolism to be able to survive and keep proliferating under conditions of nutrient stress. We show that PKCζ deficiency promotes the plasticity necessary for cancer cells to reprogram their metabolism to utilize glutamine through the serine biosynthetic pathway in the absence of glucose. PKCζ represses the expression of two key enzymes of the pathway, PHGDH and PSAT1, and phosphorylates PHGDH at key residues to inhibit its enzymatic activity. Interestingly, the loss of PKCζ in mice results in enhanced intestinal tumorigenesis and increased levels of these two metabolic enzymes, whereas patients with low levels of PKCζ have a poor prognosis. Furthermore, PKCζ and caspase-3 activities are correlated with PHGDH levels in human intestinal tumors. Taken together, this demonstrates that PKCζ is a critical metabolic tumor suppressor in mouse and human cancer.


Asunto(s)
Adenocarcinoma/metabolismo , Adenoma/metabolismo , Neoplasias del Colon/metabolismo , Proteína Quinasa C/metabolismo , Proteína de la Poliposis Adenomatosa del Colon/genética , Proteína de la Poliposis Adenomatosa del Colon/metabolismo , Animales , Vías Biosintéticas , Transformación Celular Neoplásica , Glucosa/metabolismo , Humanos , Ratones , Serina/biosíntesis , Organismos Libres de Patógenos Específicos , Estrés Fisiológico
5.
Proc Natl Acad Sci U S A ; 108(6): 2361-5, 2011 Feb 08.
Artículo en Inglés | MEDLINE | ID: mdl-21262837

RESUMEN

Pten inactivation promotes cell survival in leukemia cells by activating glycolytic metabolism. We found that targeting ribosomal protein S6 kinase 1 (S6K1) in Pten-deficient cells suppressed glycolysis and induced apoptosis. S6K1 knockdown decreased expression of HIF-1α, and HIF-1α was sufficient to restore glycolysis and survival of cells lacking S6K1. In the Pten(fl/fl) Mx1-Cre(+) mouse model of leukemia, S6K1 deletion delayed the development of leukemia. Thus, S6K1 is a critical mediator of glycolytic metabolism, cell survival, and leukemogenesis in Pten-deficient cells.


Asunto(s)
Apoptosis , Glucólisis , Leucemia/enzimología , Proteínas de Neoplasias/metabolismo , Fosfohidrolasa PTEN/metabolismo , Proteínas Quinasas S6 Ribosómicas 90-kDa/metabolismo , Animales , Línea Celular Tumoral , Modelos Animales de Enfermedad , Técnicas de Silenciamiento del Gen , Subunidad alfa del Factor 1 Inducible por Hipoxia/genética , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Leucemia/genética , Ratones , Ratones Noqueados , Proteínas de Neoplasias/genética , Fosfohidrolasa PTEN/genética , Proteínas Quinasas S6 Ribosómicas 90-kDa/genética
6.
Cancer Biol Ther ; 10(12): 1256-61, 2010 Dec 15.
Artículo en Inglés | MEDLINE | ID: mdl-20935504

RESUMEN

We performed a high-throughput screen to identify compounds with a selective ability to induce apoptosis in Akt-expressing cells without disrupting Bcl-xL-dependent survival. Results showed that a screening strategy based on Alamar Blue underrepresented the viability of Bcl-xL-expressing cells relative to Akt-expressing cells, possibly due to metabolic differences between the two cell survival programs. Using an alternative screen based on plasma membrane integrity, we identified several compounds that target Akt-dependent survival without toxic effect to Bcl-xL-dependent survival. These compounds enhanced the cytotoxic potential of rapamycin, a chemotherapeutic that inhibits survival signaling downstream of Akt. The results demonstrate a screening method and the subsequent identification of two compounds with selective activity in counteracting Akt-dependent cell survival.


Asunto(s)
Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Ensayos Analíticos de Alto Rendimiento , Proteínas Proto-Oncogénicas c-akt/metabolismo , Sirolimus/farmacología , Proteína bcl-X/metabolismo , Animales , Caspasa 3/metabolismo , Línea Celular , Membrana Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Descubrimiento de Drogas , Ensayos de Selección de Medicamentos Antitumorales/métodos , Ratones , Oxazinas , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/antagonistas & inhibidores , Transducción de Señal/efectos de los fármacos , Xantenos , Proteína bcl-X/genética
7.
Endocr Relat Cancer ; 17(4): R287-304, 2010 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-20699334

RESUMEN

Cancer biologists' search for new chemotherapy targets is reinvigorating the study of how cancer cell metabolism determines both oncogenic potential and chemotherapeutic responses. Oncogenic metabolic programs support the bioenergetics associated with resistance to programed cell death and provide biosynthetic building blocks for cell growth and mitogenesis. Both signal transduction pathway activation and direct mutations in key metabolic enzymes can activate the metabolic programs that support cancer cell growth. Cancer-associated metabolic programs include glycolysis, glutamine oxidation, and fatty acid metabolism. Recent observations are revealing the regulatory mechanisms that activate cancer-associated metabolism, and the competitive advantages provided to transformed cells by their metabolic programs. In this study, we review recent results illustrating the mechanisms and functional impact of each of these oncogenic metabolic programs in cancer cell growth and survival.


Asunto(s)
Transformación Celular Neoplásica/metabolismo , Ácidos Grasos/metabolismo , Glutamina/metabolismo , Neoplasias/metabolismo , Transformación Celular Neoplásica/patología , Metabolismo Energético/fisiología , Glucólisis/fisiología , Humanos , Neoplasias/patología , Transducción de Señal
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