Chromosomal instability (CIN) is a hallmark of cancer. While low levels of CIN can be tumor promoting, high levels of CIN cause cell death and tumor suppression. The widely used chemotherapeutic paclitaxel (TaxolTM) exerts its anti-cancer effects by increasing CIN above a maximally tolerated threshold. One significant outstanding question is whether the p53 tumor suppressor is required for the cell death and tumor suppression caused by high CIN. Both p53 loss and reduction of the mitotic kinesin CENP-E cause low CIN. Combining both genetic insults in the same cell leads to high CIN. Here we test whether high CIN causes cell death and tumor suppression even in the absence p53. Despite a surprising sex-specific difference in tumor spectrum and latency in p53 heterozygous animals, these studies demonstrate that p53 is not required for high CIN to induce tumor suppression. Pharmacological induction of high CIN results in equivalent levels of cell death due to loss of essential chromosomes in p53+/+ and p53-/- cells, further demonstrating that high CIN elicits cell death independently of p53 function. Implications: These results provide support for the efficacy of anti-cancer therapies that induce high CIN, even in tumors that lack functional p53.

中文翻译：

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p53 不是染色体高度不稳定性引起的细胞死亡和肿瘤抑制所必需的

染色体不稳定（CIN）是癌症的一个标志。虽然低水平的 CIN 可能促进肿瘤生长，但高水平的 CIN 会导致细胞死亡和肿瘤抑制。广泛使用的化疗药物紫杉醇 (TaxolTM) 通过将 CIN 增加到最大耐受阈值以上来发挥抗癌作用。一个重要的悬而未决的问题是高CIN引起的细胞死亡和肿瘤抑制是否需要p53肿瘤抑制因子。p53 缺失和有丝分裂驱动蛋白 CENP-E 减少都会导致 CI​​N 降低。在同一个细胞中结合两种基因损伤会导致高 CIN。在这里，我们测试即使在缺乏 p53 的情况下，高 CIN 是否也会导致细胞死亡和肿瘤抑制。尽管 p53 杂合动物的肿瘤谱和潜伏期存在令人惊讶的性别特异性差异，但这些研究表明，高 CIN 诱导肿瘤抑制并不需要 p53。由于 p53+/+ 和 p53-/- 细胞中必需染色体的丢失，高 CIN 的药理学诱导导致同等水平的细胞死亡，进一步证明高 CIN 引起的细胞死亡与 p53 功能无关。意义：这些结果为诱导高 CIN 的抗癌疗法的有效性提供了支持，即使在缺乏功能性 p53 的肿瘤中也是如此。