Synthetic lethal metabolic targeting of cellular senescence in cancer therapy.
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 Eµ-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.
Charité-Universitätsmedizin Berlin, Molekulares Krebsforschungszentrum, Augustenburger Platz 1, 13353 Berlin, Germany.
Jan R
JR
Dörr
Yong
Y
Yu
Maja
M
Milanovic
Gregor
G
Beuster
Christin
C
Zasada
J Henry M
JH
Däbritz
Jan
J
Lisec
Dido
D
Lenze
Anne
A
Gerhardt
Katharina
K
Schleicher
Susanne
S
Kratzat
Bettina
B
Purfürst
Stefan
S
Walenta
Wolfgang
W
Mueller-Klieser
Markus
M
Gräler
Michael
M
Hummel
Ulrich
U
Keller
Andreas K
AK
Buck
Bernd
B
Dörken
Lothar
L
Willmitzer
Maurice
M
Reimann
Stefan
S
Kempa
Soyoung
S
Lee
Clemens A
CA
Schmitt
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001343:Autophagy / Q000187:drug effects; D053454:Caspase 12 / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism; D016922:Cellular Senescence / Q000187:drug effects; D004195:Disease Models, Animal; D059865:Endoplasmic Reticulum Stress; D005260:Female; D005947:Glucose / Q000378:metabolism*; D016393:Lymphoma, B-Cell / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D059748:Proteolysis; D013312:Stress, Physiological; D015996:Survival Rate
D053454:Caspase 12; D053148:Caspase 3; D005947:Glucose