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Détermination des mécanismes d’échappement à la mort par autophagie lors des étapes très précoces de transformation de cellules sénescentes en cellules tumorales
| Content Provider | Semantic Scholar |
|---|---|
| Author | Deruy, Emeric |
| Copyright Year | 2011 |
| Abstract | Senescence is a non proliferative state that occurs in response to telomere shortening, oxidative stress or oncogenic activation. Whereas senescence is generally considered as an irreversible growth arrest, we recently reported, using Normal Human Epidermal Keratinocytes (NHEKs), that few senescent cells can spontaneously reactivate a mitotic process to generate so-called post-senescence emergent cells which are transformed and able to form skin hyperplasia in nude mice. In the first part of this work, we have investigated the outcome of the majority of senescent cells that do not generate emergent cells. We highlighted that senescent cells massively die during the growth arrest. Interestingly, the death is not associated with apoptotic or necrotic features but involves the elimination of numerous vital cells components by macroautophagy. We next investigated the mechanism that activates the autophagic programmed cell death in senescent keratinocytes. We show that oxidative stress occuring during senescence causes numerous cellular damages, notably to nucleus and mitochondria, that activate the macroautophagic process to ultimately lead to the death. In the last part of this work, we have investigated the relationship between oxidative stress and macroautophagy during the generation of post-senescence emergent cells. We show that progenitors of these neoplastic cells display less reactive oxygen species (ROS) production than other senescent keratinocytes, and hence escape autophagic cell death. However, in order to generate PS emergent cells, they have to maintain an housekeeping autophagic activity. Taken together, these results indicate that the outcome of a senescent cell is driven by its ROS level. A high ROS level induces a high and lethal activation of autophagy. At a lower ROS level, the cell activates a moderated autophagy that fails to induce death but favors the elimination of oxidized proteins and organelles. By this way, this cell becomes permissive to neoplastic evolution consecutively to the putative oxidative alteration of oncogenes, tumor suppressor genes or other crucial cell regulators. |
| File Format | PDF HTM / HTML |
| Alternate Webpage(s) | https://ori-nuxeo.univ-lille1.fr/nuxeo/site/esupversions/f96076b5-7db4-45b8-b3df-7118eead8b46 |
| Language | English |
| Access Restriction | Open |
| Content Type | Text |
| Resource Type | Article |
