Synthetic lethal metabolic targeting of cellular senescence in cancer therapy
Synthetic lethal metabolic targeting of cellular senescence in cancer therapy
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DOI：
10.1038/nature12437
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发表时间：
2013-09-19
期刊：
影响因子：
64.8
通讯作者：
Schmitt, Clemens A.
中科院分区：
文献类型：
--
作者：
Doerr, Jan R.;Yu, Yong;Schmitt, Clemens A.
激活的癌基因和抗癌化疗诱导细胞衰老，这是一种以S期进入阻断组蛋白3赖氨酸9三甲基化（H3 K9 me 3）为特征的活细胞终末生长停滞（1，2）。虽然治疗诱导的衰老（TIS）改善了长期结果（3），但衰老肿瘤细胞的潜在有害特性使其定量消除成为治疗优先事项。在这里，我们使用Em-myc转基因小鼠淋巴瘤模型，其中TIS依赖于H3 K9组蛋白甲基转移酶Suv 39 h1，以显示体外和体内衰老相关的代谢重编程的机制和治疗开发。在衰老诱导化疗后，TIS活性淋巴瘤而非TIS不活性Suv 39 h1（-）淋巴瘤显示葡萄糖利用增加和ATP产生更高。我们证明这与大量蛋白毒性应激有关，这是先前描述的衰老相关分泌表型（SASP）的结果（4-6）。产生SASP的TIS细胞表现出内质网应激、未折叠蛋白反应（UPR）和增加的泛素化，从而以急性能量消耗方式靶向毒性蛋白进行自噬。因此，TIS淋巴瘤，不像衰老模型，缺乏一个强大的SASP反应，更敏感的阻断葡萄糖利用或自噬，这导致他们的选择性消除通过caspase-12和caspase-3介导的内质网相关的凋亡。因此，在体内对TIS诱导的这些代谢需求的药理学靶向促进肿瘤消退并进一步改善治疗结果。这些发现揭示了TIS的高分解代谢性质，其可通过合成致死代谢靶向进行治疗。
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)(1,2). Although therapy-induced senescence (TIS) improves long-term outcomes(3), 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 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(4-6). 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.