Biozentrum, University of Basel, 4056 Basel, Switzerland.
Institute of Pathology, University Hospital Basel, University of Basel, 4056 Basel, Switzerland.
Mol Biol Cell. 2018 May 1;29(9):1031-1047. doi: 10.1091/mbc.E17-10-0577.
Although aneuploidy is poorly tolerated during embryogenesis, aneuploidy and whole chromosomal instability (CIN) are common hallmarks of cancer, raising the question of how cancer cells can thrive in spite of chromosome aberrations. Here we present a comprehensive and quantitative proteomics analysis of isogenic DLD-1 colorectal adenocarcinoma cells lines, aimed at identifying cellular responses to changes in ploidy and/or CIN. Specifically, we compared diploid (2N) and tetraploid (4N) cells with posttetraploid aneuploid (PTA) clones and engineered trisomic clones. Our study provides a comparative data set on the proteomes and phosphoproteomes of the above cell lines, comprising several thousand proteins and phosphopeptides. In comparison to the parental 2N line, we observed changes in proteins associated with stress responses and with interferon signaling. Although we did not detect a conspicuous protein signature associated with CIN, we observed many changes in phosphopeptides that relate to fundamental cellular processes, including mitotic progression and spindle function. Most importantly, we found that most changes detectable in PTA cells were already present in the 4N progenitor line. This suggests that activation of mitotic pathways through hyper-phosphorylation likely constitutes an important response to chromosomal burden. In line with this conclusion, cells with extensive chromosome gains showed differential sensitivity toward a number of inhibitors targeting cell cycle kinases, suggesting that the efficacy of anti-mitotic drugs may depend on the karyotype of cancer cells.
虽然非整倍体在胚胎发生过程中不能很好地耐受，但非整倍体和全染色体不稳定性（CIN）是癌症的常见特征，这就提出了一个问题，即癌细胞如何能够在染色体异常的情况下茁壮成长。在这里，我们对同源的 DLD-1 结直肠腺癌细胞系进行了全面和定量的蛋白质组学分析，旨在鉴定细胞对倍性和/或 CIN 变化的反应。具体来说，我们比较了二倍体（2N）和四倍体（4N）细胞与后四倍体非整倍体（PTA）克隆和工程化的三体克隆。我们的研究提供了上述细胞系的蛋白质组和磷酸蛋白质组的比较数据集，包括数千种蛋白质和磷酸肽。与亲本 2N 系相比，我们观察到与应激反应和干扰素信号相关的蛋白质发生变化。尽管我们没有检测到与 CIN 相关的明显蛋白质特征，但我们观察到许多与基本细胞过程相关的磷酸肽发生变化，包括有丝分裂进展和纺锤体功能。最重要的是，我们发现 PTA 细胞中可检测到的大多数变化在 4N 祖细胞系中已经存在。这表明通过过度磷酸化激活有丝分裂途径可能是对染色体负担的重要反应。与这一结论一致的是，具有广泛染色体增益的细胞对许多针对细胞周期激酶的抑制剂表现出不同的敏感性，这表明抗有丝分裂药物的疗效可能取决于癌细胞的核型。
