New metabolism-targeting strategies against diabetes, lung cancer and aging

Resumen

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