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Inhibiting autophagy: a new line to fight cellular senescence?

There is a new development in the search for senolytic molecules and in the understanding of their mechanisms of action. Researchers from the Frédéric Joliot Institute have identified ouabain and chloroquine as two selective senolytic molecules that are effective in eliminating certain senescent cells. The study has been published in the journal Aging Cell.

Published on 15 March 2022

​A key mechanism of aging, cellular senescence is a change in the behavior of cells that blocks their proliferation in response to stresses that can lead to cancer. It is an anti-tumor barrier. For example, the V600E mutation of the BRAF kinase (B-RAF-V600E), which is oncogenic and present in 50% of melanomas, initially induces melanocyte senescence. Senescent melanocytes constitute moles, which are benign lesions that persist for decades and very rarely develop into melanoma. However, a quarter of melanomas are associated with a pre-existing mole, which implies an escape from senescence of melanocytes that continue their oncogenic evolution.

In some contexts, the persistence of senescent cells promotes tumorigenesis or prevents tissue regeneration, thus participating in aging.

How to delay the emergence or evolution of senescence-related pathologies? 

By specifically eliminating senescent cells thanks, for example, to molecules that can be used as drugs: senolytics. This innovative approach is promising in the fight against carcinogenesis and aging, as shown by numerous studies based on animal models.

From the screening of a drug repositioning library, researchers from the Senescence and Genome stability team (I2BC department), in collaboration with a researcher from the SCBM department, have identified several cardioglycosides (including ouabain) as potential senolytics of cells whose senescence is triggered by BRAF-V600E. Cardioglycosides are inhibitors of the sodium-potassium ATPase pump (Na,K ATPase) that are used in the treatment of cardiac disorders. They inhibit ion transport by the ATPase, and thus the membrane potential difference, and trigger signal transduction pathways. In the cellular model used by the I2BC researchers, the senolytic action is not mediated by inhibition of ion transport, but by activation of transduction pathways.

But why are cardioglycosides, such as ouabain, specifically toxic to cells that express BRAF-V600E?

The researchers showed in this study that BRAF-V600E expression increases endoplasmic reticulum stress and autophagy in senescent cells. They demonstrated that ouabain affects senescence by inhibiting autophagy, probably via the signal transduction pathways identified in the study. Thus, activation of autophagy by BRAF-V600E sensitizes the cell to senolysis. Other autophagy inhibitors should therefore have senolytic activity. And it is the case! Indeed, the team shows in this study that two compounds, bafilomycin A1 and especially chloroquine have a senolytic activity.

This study shows the importance of characterizing the mechanisms that explain the specificity of action of senolytics to discover new active molecules. In the long run, the understanding of these mechanisms will allow to personalize the treatments by identifying the type of cells to be eliminated and their vulnerabilities.

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