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Circumventing senescence is associated with stem cell properties and metformin sensitivity
- Source :
- Aging Cell
- Publication Year :
- 2019
- Publisher :
- Wiley-Blackwell, 2019.
-
Abstract
- 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.
- Subjects :
- 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
Subjects
Details
- Language :
- English
- ISSN :
- 14749726 and 14749718
- Volume :
- 18
- Issue :
- 2
- Database :
- OpenAIRE
- Journal :
- Aging Cell
- Accession number :
- edsair.doi.dedup.....6532e18d8588cf2346f581f9051742cc