Accumulating evidence indicate that increased ribosome biogenesis is a hallmark of cancer. It is well established that inhibition of any steps of ribosome biogenesis induces a nucleolar stress characterized by p53 activation and subsequent cell cycle arrest and/or cell death. However, cells derived from solid tumors have demonstrated different degree 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 with 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.

越来越多的证据表明，核糖体生物合成增加是癌症的标志。众所周知，抑制核糖体生物发生的任何步骤都会诱导以 p53 激活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，其中观察到细胞抑制作用而不是细胞凋亡。其原因尚不清楚，并且以前没有研究过核仁应激后诱导的 p53 特异性转录程序。在这里，我们证明了通过消耗必需的 rRNA 加工因子（如 LAS1L、PELP1 和 NOP2）或通过用特定的小分子抑制剂 CX-5461 抑制 RNA Pol I 来阻断 rRNA 合成，主要诱导实体瘤衍生细胞系中伴随自噬的细胞周期停滞。通过基因表达分析，我们发现 p53 协调了一个参与促进代谢重塑和自噬的转录程序，以帮助细胞在核仁应激下存活。重要的是，我们的研究表明，阻断自噬可使癌细胞对 CX-5461 抑制 RNA Pol I 显着敏感，这表明干扰自噬应被视为提高核糖体生物发生靶向疗法对 p53 阳性肿瘤的反应性的策略。