Inhibition of p53 and/or AKT as a new therapeutic approach specifically targeting ALT cancers
Inhibition of p53 and/or AKT as a new therapeutic approach specifically targeting ALT cancers
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抑制 p53 和/或 AKT 作为专门针对 ALT 癌症的新治疗方法。
DOI：
10.1007/s13238-019-0634-z
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发表时间：
2019-11-01
期刊：
影响因子：
21.1
通讯作者：
Zhao, Yong
中科院分区：
文献类型：
--
作者：
Ge, Yuanlong;Wu, Shu;Zhao, Yong
虽然大多数人类癌症通过表达端粒酶来抵消端粒缩短，但约15%的癌症通过称为端粒替代延长（ALT）的端粒非依赖性机制来维持端粒长度。在这里，我们表明，高负荷的内在DNA损伤是存在于ALT癌细胞，导致细胞凋亡的压力，通过激活p53非依赖性，但JNK/c-Myc依赖性凋亡途径。值得注意的是，表达野生型p53的ALT细胞显示出比p53缺陷型ALT细胞低得多的凋亡。从机制上讲，我们发现ALT细胞中的固有DNA损伤诱导低水平的p53，其不足以启动阿尔茨海默病相关基因的转录，但足以刺激mTORC 2的关键组分（mTOR和Rictor）的表达，这反过来导致AKT的磷酸化。活化的AKT（p-AKT）由此刺激下游抗凋亡事件。因此，p53和AKT是抑制ALT细胞自发凋亡的关键因素。事实上，抑制p53或AKT选择性地诱导ALT细胞在体外快速死亡，并且p53抑制剂严重抑制小鼠中ALT细胞异种移植肿瘤的生长。这些发现揭示了p53在抗细胞凋亡中的先前未被认识的功能，并确定了p53或AKT的抑制具有作为特异性靶向ALT癌症的治疗剂的潜力。
While the majority of all human cancers counteract telomere shortening by expressing telomerase, ~15% of all cancers maintain telomere length by a telomerase-independent mechanism known as alternative lengthening of telomeres (ALT). Here, we show that high load of intrinsic DNA damage is present in ALT cancer cells, leading to apoptosis stress by activating p53-independent, but JNK/c-Myc-dependent apoptotic pathway. Notably, ALT cells expressing wild-type p53 show much lower apoptosis than p53-deficient ALT cells. Mechanistically, we find that intrinsic DNA damage in ALT cells induces low level of p53 that is insufficient to initiate the transcription of apoptosis-related genes, but is sufficient to stimulate the expression of key components of mTORC2 (mTOR and Rictor), which in turn leads to phosphorylation of AKT. Activated AKT (p-AKT) thereby stimulates downstream anti-apoptotic events. Therefore, p53 and AKT are the key factors that suppress spontaneous apoptosis in ALT cells. Indeed, inhibition of p53 or AKT selectively induces rapid death of ALT cellsin vitro, and p53 inhibitor severely suppresses the growth of ALT-cell xenograft tumors in mice. These findings reveal a previously unrecognized function of p53 in anti-apoptosis and identify that the inhibition of p53 or AKT has a potential as therapeutics for specifically targeting ALT cancers.