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Synthetic lethal metabolic targeting of cellular senescence in cancer therapy

Official URL:https://doi.org/10.1038/nature12437
PubMed:View item in PubMed
Creators Name:Doerr, J.R. and Yu, Y. and Milanovic, M. and Beuster, G. and Zasada, C. and Daebritz, J.H.M. and Lisec, J. and Lenze, D. and Gerhardt, A. and Schleicher, K. and Kratzat, S. and Purfuerst, B. and Walenta, S. and Mueller-Klieser, W. and Graeler, M. and Hummel, M. and Keller, U. and Buck, A.K. and Doerken, B. and Willmitzer, L. and Reimann, M. and Kempa, S. and Lee, S. and Schmitt, C.A.
Journal Title:Nature
Journal Abbreviation:Nature
Volume:501
Number:7467
Page Range:421-425
Date:19 September 2013
Keywords:Animal Disease Models, Apoptosis, Autophagy, B-Cell Lymphoma, Caspase 3, Caspase 12, Cell Aging, Endoplasmic Reticulum Stress, Glucose, Physiological Stress, Proteolysis, Survival Rate, Animals, Mice
Abstract:Activated oncogenes and anticancer chemotherapy induce cellular senescence, a terminal growth arrest of viable cells characterized by S-phase entry-blocking histone 3 lysine 9 trimethylation (H3K9me3). Although therapy-induced senescence (TIS) improves long-term outcomes, potentially harmful properties of senescent tumour cells make their quantitative elimination a therapeutic priority. Here we use the Emicro-myc transgenic mouse lymphoma model in which TIS depends on the H3K9 histone methyltransferase Suv39h1 to show the mechanism and therapeutic exploitation of senescence-related metabolic reprogramming in vitro and in vivo. After senescence-inducing chemotherapy, TIS-competent lymphomas but not TIS-incompetent Suv39h1(-) lymphomas show increased glucose utilization and much higher ATP production. We demonstrate that this is linked to massive proteotoxic stress, which is a consequence of the senescence-associated secretory phenotype (SASP) described previously. SASP-producing TIS cells exhibited endoplasmic reticulum stress, an unfolded protein response (UPR), and increased ubiquitination, thereby targeting toxic proteins for autophagy in an acutely energy-consuming fashion. Accordingly, TIS lymphomas, unlike senescence models that lack a strong SASP response, were more sensitive to blocking glucose utilization or autophagy, which led to their selective elimination through caspase-12- and caspase-3-mediated endoplasmic-reticulum-related apoptosis. Consequently, pharmacological targeting of these metabolic demands on TIS induction in vivo prompted tumour regression and improved treatment outcomes further. These findings unveil the hypercatabolic nature of TIS that is therapeutically exploitable by synthetic lethal metabolic targeting.
ISSN:0028-0836
Publisher:Nature Publishing Group (U.K.)
Item Type:Article

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