p53 induces a survival transcriptional response after nucleolar stress.
p53 induces a survival transcriptional response after nucleolar stress.
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DOI：
10.1091/mbc.e21-05-0251
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发表时间：
2021-10-01
影响因子：
3.3
通讯作者：
Denicourt C
中科院分区：
文献类型：
--
作者：
Liao H;Gaur A;Mauvais C;Denicourt C
越来越多的证据表明，核糖体生物合成增加是癌症的标志。已经确定的是，核糖体生物发生的任何步骤的抑制诱导以p53活化和随后的细胞周期停滞和/或细胞死亡为特征的核仁应激。然而，来自实体瘤的细胞已经表现出对核糖体生物发生抑制的不同程度的敏感性，其中观察到细胞生长抑制作用而不是凋亡。其原因尚不清楚，核仁应激后诱导的p53特异性转录程序以前没有研究过。在这里，我们证明了通过消耗必需的rRNA加工因子如LAS 1 L，PELP 1和NOP 2或通过用特异性小分子抑制剂CX-5461抑制RNA Pol I来阻断rRNA合成，主要诱导细胞周期停滞，伴随着实体瘤衍生细胞系中的自噬。利用基因表达分析，我们发现p53协调了一个转录程序，参与促进代谢重塑和自噬，以帮助细胞在核仁压力下生存。重要的是，我们的研究表明，阻断自噬可显著提高癌细胞对CX-5461抑制RNA Pol I的敏感性，这表明干扰自噬应被视为提高p53阳性肿瘤中核糖体生物发生靶向治疗反应性的一种策略。
Accumulating evidence indicates that increased ribosome biogenesis is a hallmark of cancer. It is well established that inhibition of any steps of ribosome biogenesis induces nucleolar stress characterized by p53 activation and subsequent cell cycle arrest and/or cell death. However, cells derived from solid tumors have demonstrated different degrees of sensitivity to ribosome biogenesis inhibition, where cytostatic effects rather than apoptosis are observed. The reason for this is not clear, and the p53-specific transcriptional program induced after nucleolar stress has not been previously investigated. Here we demonstrate that blocking rRNA synthesis by depletion of essential rRNA processing factors such as LAS1L, PELP1, and NOP2 or by inhibition of RNA Pol I with the specific small molecule inhibitor CX-5461, mainly induce cell cycle arrest accompanied by autophagy in solid tumor–derived cell lines. Using gene expression analysis, we find that p53 orchestrates a transcriptional program involved in promoting metabolic remodeling and autophagy to help cells survive under nucleolar stress. Importantly, our study demonstrates that blocking autophagy significantly sensitizes cancer cells to RNA Pol I inhibition by CX-5461, suggesting that interfering with autophagy should be considered a strategy to heighten the responsiveness of ribosome biogenesis–targeted therapies in p53-positive tumors.