Department of Cellular & Molecular Physiology, Penn State College of Medicine, Hershey, PA 17033, USA.
A.J. Drexel Autism Institute, Drexel University, Philadelphia, PA 19104, USA.
Cell Rep. 2019 Aug 20;28(8):1971-1980.e8. doi: 10.1016/j.celrep.2019.07.084.
Reprogrammed metabolism and cell cycle dysregulation are two cancer hallmarks. p16 is a cell cycle inhibitor and tumor suppressor that is upregulated during oncogene-induced senescence (OIS). Loss of p16 allows for uninhibited cell cycle progression, bypass of OIS, and tumorigenesis. Whether p16 loss affects pro-tumorigenic metabolism is unclear. We report that suppression of p16 plays a central role in reprogramming metabolism by increasing nucleotide synthesis. This occurs by activation of mTORC1 signaling, which directly mediates increased translation of the mRNA encoding ribose-5-phosphate isomerase A (RPIA), a pentose phosphate pathway enzyme. p16 loss correlates with activation of the mTORC1-RPIA axis in multiple cancer types. Suppression of RPIA inhibits proliferation only in p16-low cells by inducing senescence both in vitro and in vivo. These data reveal the molecular basis whereby p16 loss modulates pro-tumorigenic metabolism through mTORC1-mediated upregulation of nucleotide synthesis and reveals a metabolic vulnerability of p16-null cancer cells.
重新编程的代谢和细胞周期失调是两种癌症的特征。p16 是一种细胞周期抑制剂和肿瘤抑制因子，在癌基因诱导的衰老（OIS）期间上调。p16 的缺失允许细胞周期不受抑制地进展，绕过 OIS，并导致肿瘤发生。p16 的缺失是否会影响促肿瘤发生的代谢尚不清楚。我们报告称，通过增加核苷酸合成，p16 的抑制在重新编程代谢中起着核心作用。这是通过激活 mTORC1 信号转导来实现的，该信号转导直接介导编码核糖-5-磷酸异构酶 A（RPIA）的 mRNA 的翻译增加，RPIA 是戊糖磷酸途径中的一种酶。在多种癌症类型中，p16 的缺失与 mTORC1-RPIA 轴的激活相关。抑制 RPIA 仅在 p16 低表达的细胞中通过体外和体内诱导衰老来抑制增殖。这些数据揭示了 p16 缺失通过 mTORC1 介导的核苷酸合成上调来调节促肿瘤发生代谢的分子基础，并揭示了 p16 缺失的癌细胞在代谢上的脆弱性。
