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Inhibition of RNA Polymerase I as a Therapeutic Strategy to Promote Cancer-Specific Activation of p53

机译：抑制RNA聚合酶I作为促进p53癌症特异性激活的治疗策略

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摘要

Increased transcription of ribosomal RNA genes (rDNA) by RNA Polymerase I is a common feature of human cancer, but whether it is required for the malignant phenotype remains unclear. We show that rDNA transcription can be therapeutically targeted with the small molecule CX-5461 to selectively kill B-lymphoma cells in vivo while maintaining a viable wild-type B cell population. The therapeutic effect is a consequence of nucleolar disruption and activation of p53-dependent apoptotic signaling. Human leukemia and lymphoma cell lines also show high sensitivity to inhibition of rDNA transcription that is dependent on p53 mutational status. These results identify selective inhibition of rDNA transcription as a therapeutic strategy for the cancer specific activation of p53 and treatment of hematologic malignancies.
机译：RNA聚合酶I增加核糖体RNA基因（rDNA）的转录是人类癌症的普遍特征，但尚不清楚恶性表型是否需要。我们显示，rDNA转录可以治疗性靶向小分子CX-5461，以在体内选择性杀死B淋巴瘤细胞，同时保持可行的野生型B细胞群体。该治疗效果是核仁破坏和激活p53依赖性凋亡信号的结果。人白血病和淋巴瘤细胞系还显示出对依赖p53突变状态的rDNA转录抑制的高度敏感性。这些结果确定了选择性抑制rDNA转录作为p53癌症特异性激活和血液系统恶性肿瘤治疗的治疗策略。

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