Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Oncogene. 2014 Jun 12;33(24):3183-94. doi: 10.1038/onc.2013.273. Epub 2013 Jul 15.
Normal cells possess adaptive mechanisms to couple energy availability with cell growth (cell size increase) and survival, and imbalances are associated with major diseases such as cancer. Inactivation of critical regulators involved in energy stress response, including adenosine monophosphate-activated protein kinase (AMPK), liver kinase B1 (LKB1), tuberous sclerosis complex 1 (TSC1) and tuberous sclerosis complex 2 (TSC2), leads to uncontrolled cell growth yet increased apoptosis under energy stress. These energy stress regulators are also important in tumor suppression and metabolism. Here, we show that forkhead box O (FoxO) transcription factor, a central regulator of tumor suppression and metabolism, plays a unique role in energy stress response. FoxOs inhibit the mammalian target of rapamycin complex 1 (mTORC1), a key regulator of cell growth, under energy stress, and inactivation of FoxOs alleviates energy stress-mediated mTORC1 repression. Surprisingly, unlike AMPK-, Lkb1- or Tsc1/2-deficient cells, FoxO-deficient cells exhibit decreased apoptosis under energy stress. FoxOs operate to inhibit mTORC1 signaling and cell survival independent of AMPK and TSC. Integrated transcriptomic and functional analyses identified BCL2/adenovirus E1B 19 kDa protein-interacting protein 3 (BNIP3)-a negative regulator of both Rheb and Bcl2 prosurvival family members-as a key downstream target of FoxOs to inhibit mTORC1 function and promote apoptosis in response to energy stress. We show that p38β, but not AMPK, is likely to function upstream of FoxO-BNIP3 to mediate energy stress response. Finally, we reveal that low expression of FoxO or BNIP3 correlates with poor clinical outcomes in renal cancer patients. Together, our study uncovers a novel signaling circuit functioning to mediate cellular energy responses to control cell growth and survival. These findings also have important implications to human cancers.
正常细胞具有将能量可用性与细胞生长（细胞大小增加）和存活相偶联的适应机制，失衡与癌症等重大疾病有关。参与能量应激反应的关键调节因子的失活，包括单磷酸腺苷激活蛋白激酶（AMPK）、肝激酶 B1（LKB1）、结节性硬化复合物 1（TSC1）和结节性硬化复合物 2（TSC2），导致能量应激下不受控制的细胞生长和凋亡增加。这些能量应激调节剂在肿瘤抑制和代谢中也很重要。在这里，我们表明叉头框 O（FoxO）转录因子，一种肿瘤抑制和代谢的核心调节剂，在能量应激反应中发挥独特的作用。FoxOs 在能量应激下抑制哺乳动物雷帕霉素靶蛋白复合物 1（mTORC1），mTORC1 是细胞生长的关键调节剂，FoxOs 的失活缓解了能量应激介导的 mTORC1 抑制。令人惊讶的是，与 AMPK-、Lkb1-或 Tsc1/2 缺陷细胞不同，FoxO 缺陷细胞在能量应激下凋亡减少。FoxOs 通过独立于 AMPK 和 TSC 来抑制 mTORC1 信号和细胞存活。综合转录组学和功能分析确定了 BCL2/腺病毒 E1B 19 kDa 蛋白相互作用蛋白 3（BNIP3）-Rheb 和 Bcl2 生存家族成员的负调节剂-作为 FoxOs 的关键下游靶标，以抑制 mTORC1 功能并促进对能量应激的凋亡。我们表明，p38β，而不是 AMPK，可能在 FoxO-BNIP3 之前发挥作用，以介导能量应激反应。最后，我们揭示 FoxO 或 BNIP3 的低表达与肾癌患者的不良临床结果相关。总之，我们的研究揭示了一种新的信号通路，用于介导细胞对能量的反应，以控制细胞生长和存活。这些发现对人类癌症也有重要意义。
