Metabolic stress is a barrier to Epstein–Barr virus-mediated B-cell immortalization
| Autor: | Joshua E. Messinger, Jeffrey C. Rathmell, Micah A. Luftig, Rigel J. Kishton, Pavel A. Nikitin, Amy Y Hafez, Karyn McFadden |
|---|---|
| Rok vydání: | 2016 |
| Předmět: |
DNA Replication
0301 basic medicine Senescence Herpesvirus 4 Human DNA damage Cell Respiration Oxidative phosphorylation Deoxyglucose Mechanistic Target of Rapamycin Complex 1 medicine.disease_cause 03 medical and health sciences 0302 clinical medicine Stress Physiological hemic and lymphatic diseases Glucose import Autophagy medicine Humans Metabolomics Cellular Senescence Cell Proliferation B-Lymphocytes Multidisciplinary biology TOR Serine-Threonine Kinases Glucose transporter Dimethylformamide Cell Cycle Checkpoints Oncogenes Cell Transformation Viral Epstein–Barr virus Mitochondria Cell biology 030104 developmental biology PNAS Plus Multiprotein Complexes 030220 oncology & carcinogenesis biology.protein GLUT1 Tumor Suppressor Protein p53 Transcriptome DNA Damage Signal Transduction Transcription Factors |
| Zdroj: | Proceedings of the National Academy of Sciences. 113 |
| ISSN: | 1091-6490 0027-8424 |
| Popis: | Epstein-Barr virus (EBV) is an oncogenic herpesvirus that has been causally linked to the development of B-cell and epithelial malignancies. Early after infection, EBV induces a transient period of hyperproliferation that is suppressed by the activation of the DNA damage response and a G1/S-phase growth arrest. This growth arrest prevents long-term outgrowth of the majority of infected cells. We developed a method to isolate and characterize infected cells that arrest after this early burst of proliferation and integrated gene expression and metabolic profiling to gain a better understanding of the pathways that attenuate immortalization. We found that the arrested cells have a reduced level of mitochondrial respiration and a decrease in the expression of genes involved in the TCA cycle and oxidative phosphorylation. Indeed, the growth arrest in early infected cells could be rescued by supplementing the TCA cycle. Arrested cells were characterized by an increase in the expression of p53 pathway gene targets, including sestrins leading to activation of AMPK, a reduction in mTOR signaling, and, consequently, elevated autophagy that was important for cell survival. Autophagy was also critical to maintain early hyperproliferation during metabolic stress. Finally, in assessing the metabolic changes from early infection to long-term outgrowth, we found concomitant increases in glucose import and surface glucose transporter 1 (GLUT1) levels, leading to elevated glycolysis, oxidative phosphorylation, and suppression of basal autophagy. Our study demonstrates that oncogene-induced senescence triggered by a combination of metabolic and genotoxic stress acts as an intrinsic barrier to EBV-mediated transformation. |
| Databáze: | OpenAIRE |
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