Diminished origin-licensing capacity specifically sensitizes tumor cells to replication stress.
Diminished origin-licensing capacity specifically sensitizes tumor cells to replication stress.
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DOI：
10.1158/1541-7786.mcr-12-0491
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发表时间：
2013-04
期刊：
影响因子：
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通讯作者：
Jeggo PA
中科院分区：
文献类型：
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作者：
Zimmerman KM;Jones RM;Petermann E;Jeggo PA
以前的研究表明，休眠的许可复制起点可以被利用，以提高复制压力的恢复。由于肿瘤细胞表达高水平的来源许可蛋白，我们研究了这些因子的消耗是否可能特异性地使肿瘤细胞与非肿瘤细胞敏感。与以前的研究结果一致，我们观察到，与四种非肿瘤细胞系相比，三种肿瘤来源的细胞系过表达ORC 1（许可组分），并且需要更高水平的ORC 1来维持肿瘤细胞的活力。我们确定了每个品系的siRNA介导的敲低条件，其最大限度地降低了ORC 1，但不影响生存力，我们认为这将最佳地消除休眠起源。ORCl耗尽使肿瘤衍生的细胞对羟基脲（HU）和H2 O2超敏，但不影响非肿瘤细胞系的敏感性。在ORC 6或CDC 6耗尽后观察到类似的结果。此外，p53和ORC 1的共同消耗适度地损害了1BR 3 hTERT非肿瘤成纤维细胞的活力，并且更显著地引起对HU的超敏反应。最后，c-Myc癌基因的过度表达与非肿瘤BJhTERT细胞中ORC 1的缺失相结合降低了生存力。总的来说，这些发现表明肿瘤细胞可能依赖于来源许可能力，这表明许可因素可能代表基于药物的癌症治疗的靶点。
Previous studies have shown that dormant licensed replication origins can be exploited to enhance recovery from replication stress. Since tumour cells express high levels of origin licensing proteins, we examined whether depletion of such factors might specifically sensitise tumour versus non-tumour cells. Consistent with previous findings, we observed that three tumour-derived cell lines overexpress ORC1, a licensing component, compared to four non-tumour cell lines and that a greater level of ORC1 was required to maintain viability in the tumour cells. We determined siRNA-mediated knockdown conditions for each line that maximally reduced ORC1 but did not impact upon viability, which we considered would optimally deplete dormant origins. ORC1 depletion hypersensitised the tumour-derived cells to hydroxyurea (HU) and H202 but did not affect the sensitivity of the non-tumour lines. Similar results were observed following depletion of ORC6 or CDC6. Further, co-depletion of p53 and ORC1 modestly impaired viability of 1BR3hTERT non-tumour fibroblasts and more dramatically caused hypersensitivity to HU. Finally, overexpression of the c-Myc oncogene combined with ORC1 depletion in non-tumour BJhTERT cells diminished viability. Collectively, these findings suggest that tumour cells may have a reliance on origin licensing capacity, suggesting that licensing factors could represent a target for drug-based cancer therapy.