Mañana, JUEVES, 24 DE ABRIL, el sistema se apagará debido a tareas habituales de mantenimiento a partir de las 9 de la mañana. Lamentamos las molestias.
New metabolism-targeting strategies against diabetes, lung cancer and aging
Title (trans.)
Nuevas estrategias dirigidas al metabolismo contra la diabetes, cáncer de pulmón y envejecimientoAuthor
Costa Machado, Luís FilipeAdvisor
Fernández Marcos, Pablo JoséEntity
UAM. Departamento de Biología; Instituto Madrileño de Estudios Avanzados en Alimentación (IMDEA-Alimentación)Date
2020-11-06Funded by
La realización de esta tesis ha sido posible gracias a un contrato de formación predoctoral financiado por IMDEA Alimentación y la Comunidad Autónoma de Madrid (2016-2017) y gracias a una beca para la realización de estudios doctorales otorgada por la Fundación Portuguesa para la Ciencia y Tecnología (FCT‐MCTES, SFRH/BD/124022/2016) (2017- 2020Subjects
Metabolismo; Diabetes; Cáncer; Biología y Biomedicina / BiologíaNote
Tesis doctoral inédita leída en la Universidad Autónoma de Madrid, Facultad de Ciencias, Departamento de Biología. Fecha de lectura: 06-11-2020Esta tesis tiene embargado el acceso al texto completo hasta el 06-05-2022
Esta obra está bajo una licencia de Creative Commons Reconocimiento-NoComercial-SinObraDerivada 4.0 Internacional.
Abstract
In every organism, perfect balance in the metabolic reactions are vital, and alterations
in metabolic homeostasis can lead to a disruption in cellular functionality and, ultimately, to
disease. In this context, strategies aimed at correcting these imbalances and restore
normal metabolic function can be seen as powerful strategies to prevent the development
of these type of diseases. In this study, we have focused on the development of metabolic
targeting strategies to correct major metabolic disruptions and prevent the development of
diabetes, aging and cancer.
In the first part of this work, we focused on the identification of new mitochondrial
function-enhancing products. Mitochondrial dysfunction is a metabolic alteration known to
drive insulin resistance and accelerate the aging process. We first developed a protocol for
the identification of mitohormetic products capable of inducing a mild and transient
mitochondrial stress that generate a beneficial compensatory response that ultimately
improves mitochondrial fitness. Using this strategy, we identified one promising compound,
harmol, a compound from the family of β-carbolines, which proved to be efficient at
enhancing mitochondrial function in cells and improve glucose tolerance in prediabetic
mouse models. In addition to harmol, we were also able to identify a natural extract from
thyme, E29, and both products proved to highly efficient at increasing the lifespan of the
nematode C. elegans.
In the second part, we studied how SIRT1, an important deacetylase protein known for
its relevance in cellular metabolism, interferes with the development of K-RAS-driven lung
carcinoma. Although metabolism is not the primary cause underling cancer development,
important alterations can be observed during oncogenic activation. Using MEFs and human
cancer cell lines, we observed that K-RAS oncogenic activation destabilized SIRT1 protein
levels through a mechanism dependent on the activation of the MAPK pathway. Moreover,
and using transgenic mouse models, we found that, whole body SIRT1 overexpression
prior to tumor initiation works as a powerful tumor suppressor strategy in the context of KRAS
-driven lung carcinogenesis. In patients with NSCLCs, we found that SIRT1 protein
levels were positively correlated with increased overall and disease free survival
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Google Scholar:Costa Machado, Luís Filipe
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