Circumventing senescence is associated with stem cell properties and metformin sensitivity
| Autor: | Xavier Deschênes-Simard, Marie Camille Rowell, Karine Moineau-Vallée, Benjamin Le Calvé, Nabeel Bardeesy, Sebastian Igelmann, Filippos Kottakis, Maxime Parisotto, Gerardo Ferbeyre, Paloma Kalegari, Emmanuelle Saint-Germain, Véronique Bourdeau |
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| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Senescence Aging endocrine system diseases Context (language use) Mitochondrion Mice Structure-Activity Relationship 03 medical and health sciences 0302 clinical medicine Tumor Cells Cultured Animals Humans STAT3 Cellular Senescence Original Paper Dose-Response Relationship Drug biology Oncogene Stem Cells Cell Differentiation Cell Biology Original Papers Metformin 3. Good health Telomere 030104 developmental biology biology.protein Cancer research Signal transduction Stem cell 030217 neurology & neurosurgery |
| Zdroj: | Aging Cell |
| ISSN: | 1474-9726 1474-9718 |
| Popis: | Most cancers arise in old individuals, which also accumulate senescent cells. Cellular senescence can be experimentally induced by expression of oncogenes or telomere shortening during serial passage in culture. In vivo, precursor lesions of several cancer types accumulate senescent cells, which are thought to represent a barrier to malignant progression and a response to the aberrant activation of growth signaling pathways by oncogenes (oncogene toxicity). Here, we sought to define gene expression changes associated with cells that bypass senescence induced by oncogenic RAS. In the context of pancreatic ductal adenocarcinoma (PDAC), oncogenic KRAS induces benign pancreatic intraepithelial neoplasias (PanINs), which exhibit features of oncogene‐induced senescence. We found that the bypass of senescence in PanINs leads to malignant PDAC cells characterized by gene signatures of epithelial‐mesenchymal transition, stem cells, and mitochondria. Stem cell properties were similarly acquired in PanIN cells treated with LPS, and in primary fibroblasts and mammary epithelial cells that bypassed Ras‐induced senescence after reduction of ERK signaling. Intriguingly, maintenance of cells that circumvented senescence and acquired stem cell properties was blocked by metformin, an inhibitor of complex I of the electron transport chain or depletion of STAT3, a protein required for mitochondrial functions and stemness. Thus, our studies link bypass of senescence in premalignant lesions to loss of differentiation, acquisition of stemness features, and increased reliance on mitochondrial functions. |
| Databáze: | OpenAIRE |
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