The proteasome, the catalytic arm of the ubiquitin system, is regulated via its dynamic compartmentation between the nucleus and the cytoplasm, among other mechanisms. Under amino acid shortage, the proteolytic complex is translocated to the cytoplasm, where it stimulates proteolysis to supplement recycled amino acids for essential protein synthesis. This response is mediated via the mTOR pathway and the lack of the three aromatic amino acids Tyr, Trp, and Phe (YWF). mTOR activation by supplementation of the triad inhibits proteasome translocation, leading to cell death. We now show that tumoral inherent stress conditions result in translocation of the proteasome from the nucleus to the cytosol. We further show that the modulation of the signaling cascade governed by YWF is applicable also to non-starved cells by using higher concentration of the triad to achieve a surplus relative to all other amino acids. Based on these two phenomena, we found that the modulation of stress signals via the administration of YWF leads to nuclear proteasome sequestration and inhibition of growth of xenograft, spontaneous, and metastatic mouse tumor models. In correlation with the observed effect of YWF on tumors, we found – using transcriptomic and proteomic analyses – that the triad affects various cellular processes related to cell proliferation, migration, and death. In addition, Sestrin3—a mediator of YWF sensing upstream of mTOR—is essential for proteasome translocation, and therefore plays a pro-tumorigenic role, positioning it as a potential oncogene. This newly identified approach for hijacking the cellular “satiety center” carries therefore potential therapeutic implications for cancer.

蛋白酶体是泛素系统的催化臂，通过其在细胞核和细胞质之间的动态区室以及其他机制进行调节。在氨基酸短缺的情况下，蛋白水解复合物易位到细胞质，在那里它刺激蛋白水解以补充回收氨基酸以进行必需蛋白质合成。这种反应是通过 mTOR 通路和三种芳香族氨基酸 Tyr、Trp 和 Phe （YWF） 的缺乏介导的。通过补充 triad 激活 mTOR 可抑制蛋白酶体易位，导致细胞死亡。我们现在表明，肿瘤固有的应激条件导致蛋白酶体从细胞核易位到胞质溶胶。我们进一步表明，由 YWF 控制的信号级联反应的调节也适用于非饥饿细胞，通过使用更高浓度的三联体来实现相对于所有其他氨基酸的盈余。基于这两个现象，我们发现通过 YWF 的施用调节应激信号导致核蛋白酶体隔离和抑制异种移植、自发性和转移性小鼠肿瘤模型的生长。与观察到的 YWF 对肿瘤的影响相关，我们发现 - 使用转录组学和蛋白质组学分析 - 三联征影响与细胞增殖、迁移和死亡相关的各种细胞过程。此外，Sestrin3 是 mTOR 上游 YWF 感应的介质，对蛋白酶体易位至关重要，因此起着促肿瘤作用，将其定位为潜在的癌基因。因此，这种新发现的劫持细胞“饱腹感中心”的方法对癌症具有潜在的治疗意义。