Theodor Boveri Institute, Biocenter, University of Würzburg, Am Hubland, 97074 Würzburg, Germany.
Nature. 2012 Mar 28;483(7391):608-12. doi: 10.1038/nature10927.
Deregulated expression of the MYC oncoprotein contributes to the genesis of many human tumours, yet strategies to exploit this for a rational tumour therapy are scarce. MYC promotes cell growth and proliferation, and alters cellular metabolism to enhance the provision of precursors for phospholipids and cellular macromolecules. Here we show in human and murine cell lines that oncogenic levels of MYC establish a dependence on AMPK-related kinase 5 (ARK5; also known as NUAK1) for maintaining metabolic homeostasis and for cell survival. ARK5 is an upstream regulator of AMPK and limits protein synthesis via inhibition of the mammalian target of rapamycin 1 (mTORC1) signalling pathway. ARK5 also maintains expression of mitochondrial respiratory chain complexes and respiratory capacity, which is required for efficient glutamine metabolism. Inhibition of ARK5 leads to a collapse of cellular ATP levels in cells expressing deregulated MYC, inducing multiple pro-apoptotic responses as a secondary consequence. Depletion of ARK5 prolongs survival in MYC-driven mouse models of hepatocellular carcinoma, demonstrating that targeting cellular energy homeostasis is a valid therapeutic strategy to eliminate tumour cells that express deregulated MYC.
原癌蛋白 MYC 的表达失调导致了许多人类肿瘤的发生，但利用这一特性进行合理的肿瘤治疗的策略却很少。MYC 促进细胞生长和增殖，并改变细胞代谢，以增强磷脂和细胞大分子前体的供应。在这里，我们在人类和鼠类细胞系中表明，致癌水平的 MYC 依赖 AMPK 相关激酶 5（ARK5；也称为 NUAK1）来维持代谢平衡和细胞存活。ARK5 是 AMPK 的上游调节剂，通过抑制雷帕霉素靶蛋白 1（mTORC1）信号通路来限制蛋白质合成。ARK5 还维持线粒体呼吸链复合物和呼吸能力的表达，这对于有效的谷氨酰胺代谢是必需的。在表达失调的 MYC 的细胞中，抑制 ARK5 会导致细胞 ATP 水平崩溃，从而诱导多种促凋亡反应作为次要后果。ARK5 的耗竭延长了 MYC 驱动的肝癌小鼠模型的存活时间，证明靶向细胞能量稳态是消除表达失调的 MYC 的肿瘤细胞的有效治疗策略。
