SYNTHETIC LETHAL METABOLIC TARGETING OF CELLULAR SENESCENCE IN CANCER THERAPY
Jan R. Dörr, Yong Yu, Maja Milanovic, Gregor Beuster, Christin Zasada, J. Henry M. Däbritz, Jan Lisec, Dido Lenze, Anne Gerhardt, Katharina Schleicher, Susanne Kratzat, Bettina Purfürst, Stefan Walenta, Wolfgang Mueller-Klieser, Markus Gräler, Michael Hummel, Ulrich Keller, Andreas K. Buck, Bernd Dörken, Lothar Willmitzer, Maurice Reimann, Stefan Kempa, Soyoung Lee, Clemens A. Schmitt. (14-08-2013).Nature
, doi: 10.1038
Research Area C
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 Em-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 senescenceinducing chemotherapy, TIS-competent lymphomas but not TIS-incompetent Suv39h1 lymphomas showincreased glucose utilization and much higher ATP production.We demonstrate that this is linked tomassive proteotoxic stress,whichis a consequence of the senescenceassociated secretory phenotype (SASP) described previously. SASPproducing TIS cells exhibited endoplasmic reticulum stress, an unfolded protein response (UPR), and increased ubiquitination, thereby targeting toxic proteins for autophagy in an acutely energyconsuming 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 endoplasmicreticulum-related apoptosis.Consequently, pharmacological targeting of thesemetabolic demands on TISinductionin vivoprompted tumour regression and improved treatment outcomes further. These findings unveil the hypercatabolic nature of TIS that is therapeutically exploitable by synthetic lethal metabolic targeting.