Oncogene-induced cellular senescence elicits an anti-Warburg effect

Cellular senescence, an irreversible cell cycle arrest induced by a diversity of stimuli, has been considered as an innate tumor suppressing mechanism with implications and applications in cancer therapy. Using a targeted proteomics approach, we show that fibroblasts induced into senescence by expre...

Full description

Saved in:
Bibliographic Details
Published in:Proteomics (Weinheim) 2013-09, Vol.13 (17), p.2585-2596
Main Authors: Li, Mingxi, Durbin, Kenneth R., Sweet, Steve M. M., Tipton, Jeremiah D., Zheng, Yupeng, Kelleher, Neil L.
Format: Article
Language:English
Subjects:
Acetylation
Cancer
Cell biology
Cell cycle
Cell Cycle Checkpoints
Cell Line
Cell Proliferation
Cellular Senescence - genetics
Chromatin - metabolism
Chromatography, Liquid - methods
Cytosol - metabolism
Down-Regulation
Fibroblasts
Glycolysis - genetics
Glycolysis - physiology
Histones
Histones - metabolism
Humans
Medical research
Metabolism
Mitochondrial Proteins - biosynthesis
Neoplasms - genetics
Neoplasms - metabolism
Neoplasms - pathology
Oncogenes
Oxidative phosphorylation
Proteome - metabolism
Proteomics
Proteomics - methods
ras Proteins - genetics
Senescence
Tandem Mass Spectrometry - methods
Transcription, Genetic
Up-Regulation
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Cellular senescence, an irreversible cell cycle arrest induced by a diversity of stimuli, has been considered as an innate tumor suppressing mechanism with implications and applications in cancer therapy. Using a targeted proteomics approach, we show that fibroblasts induced into senescence by expression of oncogenic Ras exhibit a decrease of global acetylation on all core histones, consistent with formation of senescence‐associated heterochromatic foci. We also detected clear increases in repressive markers (e.g. >50% elevation of H3K27me2/3) along with decreases in histone marks associated with increased transcriptional expression/elongation (e.g. H3K36me2/3). Despite the increases in repressive marks of chromatin, 179 loci (of 2206 total) were found to be upregulated by global quantitative proteomics. The changes in the cytosolic proteome indicated an upregulation of mitochondrial proteins and downregulation of proteins involved in glycolysis. These alterations in primary metabolism are opposite to the well‐known Warburg effect observed in cancer cells. This study significantly improves our understanding of stress‐induced senescence and provides a potential application for triggering it in antiproliferative strategies that target the primary metabolism in cancer cells.
ISSN:1615-9853
1615-9861
DOI:10.1002/pmic.201200298