Protein kinase CK2 is a central regulator of topoisomerase I hyperphosphorylation and camptothecin sensitivity in cancer cell lines.
Protein kinase CK2 is a central regulator of topoisomerase I hyperphosphorylation and camptothecin sensitivity in cancer cell lines.
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DOI：
10.1021/bi101110e
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发表时间：
2011-02-08
期刊：
影响因子：
2.9
通讯作者：
Gjerset, Ruth A.
中科院分区：
文献类型：
--
作者：
Bandyopadhyay, Keya;Gjerset, Ruth A.
拓扑异构酶I （topo I）在合成过程中需要解开DNA，并且为喜树碱衍生的化疗药物提供了独特的靶点，包括伊立替康和拓扑替康。虽然这些药物是非常有效的抗癌药物，但一些肿瘤由于内在或获得性耐药而没有反应，这一过程仍然知之甚少。由于治疗毒性，人们对确定调节肿瘤敏感性的细胞因子感兴趣，并可能作为治疗敏感性的预测性生物标志物。在这里，我们确定丝氨酸激酶，蛋白激酶CK2，作为topo I过度磷酸化和活性的中心调节剂，以及细胞对喜树碱的敏感性。在9种癌细胞系和3种正常组织来源的细胞系中，我们观察到CK2水平与喜树碱反应性之间的一致相关性。另外两种topo - 1靶向丝氨酸激酶，蛋白激酶C和周期蛋白依赖性激酶1，没有显示出这种相关性。喜树碱敏感的癌细胞表现出高CK2活性，topo I的过度磷酸化，topo I活性升高，topo I和topo I激活剂p14ARF之间磷酸化依赖性复合物的形成升高。喜树碱耐药的癌细胞系和正常细胞系表现出较低的CK2活性，较低的topo I磷酸化，较低的topo I活性，以及无法检测到topo I/p14ARF复合物的形成。CK2的实验抑制或激活表明，CK2对于调节这些topo I特性和改变细胞对喜树碱的反应是必要和充分的。结果建立了CK2活性与喜树碱敏感性之间的因果关系，并提示CK2、topo I磷酸化或topo I/p14ARF复合物形成可以作为治疗反应性肿瘤的生物标志物。
Topoisomerase I (topo I) is required to unwind DNA during synthesis, and provides the unique target for camptothecin-derived chemotherapeutic agents, including Irinotecan and Topotecan. While these agents are highly effective anticancer agents, some tumors do not respond due to intrinsic or acquired resistance, a process that remains poorly understood. Because of treatment toxicity, there is interest in identifying cellular factors that regulate tumor sensitivity and might serve as predictive biomarkers of therapy sensitivity. Here we identify the serine kinase, protein kinase CK2, as a central regulator of topo I hyperphosphorylation and activity, and cellular sensitivity to camptothecin. In 9 cancer cell lines and 3 normal tissue-derived cell lines we observe a consistent correlation between CK2 levels and camptothecin responsiveness. Two other topo I-targeted serine kinases, protein kinase C and cyclin-dependent kinase1, do not show this correlation. Camptothecin-sensitive cancer cell lines display high CK2 activity, hyperphosphorylation of topo I, elevated topo I activity, and elevated phosphorylation-dependent complex formation between topo I and p14ARF, a topo I activator. Camptothecin-resistant cancer cell lines and normal cell lines display lower CK2 activity, lower topo I phosphorylation, lower topo I activity, and undetectable topo I/p14ARF complex formation. Experimental inhibition or activation of CK2 demonstrates that CK2 is necessary and sufficient for regulating these topo I properties and altering cellular responses to camptothecin. The results establish a cause and effect relationship between CK2 activity and camptothecin sensitivity, and suggest that CK2, topo I phosphorylation, or topo I/p14ARF complex formation could provide biomarkers of therapy responsive tumors.
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