抑制 RNA 聚合酶 I 作为一种促进 p53 肿瘤特异性激活的治疗策略。
Inhibition of RNA polymerase I as a therapeutic strategy to promote cancer-specific activation of p53.
机构信息
Division of Cancer Research, Peter MacCallum Cancer Centre, St. Andrews Place, East Melbourne, Victoria 3002, Australia.
出版信息
Cancer Cell. 2012 Jul 10;22(1):51-65. doi: 10.1016/j.ccr.2012.05.019.
Abstract
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.
摘要
核糖体 RNA 基因（rDNA）转录的增加是人类癌症的一个常见特征，但它是否是恶性表型所必需的仍不清楚。我们表明，小分子 CX-5461 可以靶向 rDNA 转录，以选择性地杀死体内的 B 淋巴瘤细胞，同时保持存活的野生型 B 细胞群体。治疗效果是核仁破坏和 p53 依赖性凋亡信号激活的结果。人类白血病和淋巴瘤细胞系也对 rDNA 转录的抑制表现出高度的敏感性，这取决于 p53 突变状态。这些结果表明，选择性抑制 rDNA 转录是激活 p53 的癌症特异性治疗策略和治疗血液恶性肿瘤的一种方法。
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