Inactivation of mirk/dyrk1b kinase targets quiescent pancreatic cancer cells.
Inactivation of mirk/dyrk1b kinase targets quiescent pancreatic cancer cells.
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DOI：
10.1158/1535-7163.mct-11-0498
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发表时间：
2011-11
影响因子：
5.7
通讯作者：
Friedman EA
中科院分区：
文献类型：
--
作者：
Ewton DZ;Hu J;Vilenchik M;Deng X;Luk KC;Polonskaia A;Hoffman AF;Zipf K;Boylan JF;Friedman EA
癌症治疗中的一个主要问题来自于对大多数化疗药物和放射相对不敏感的静止癌细胞。当这些残留的癌细胞重新进入细胞周期时，会导致肿瘤再生长或复发。早期的研究表明，丝氨酸/苏氨酸激酶Mirk/dyrk 1B的水平在静止的G 0肿瘤细胞中升高高达10倍，Mirk使用几种机制来阻断细胞周期，并且Mirk增加抗氧化基因的表达，从而降低ROS水平并增加静止的细胞活力。我们现在表明，一种新的小分子Mirk激酶抑制剂阻止肿瘤细胞在静止G 0状态下发生可逆性停滞，并使一些细胞退出静止。该抑制剂在表达Mirk的Panc 1、AsPc 1和SW 620细胞中增加了细胞周期，但在不表达Mirk的HCT 116细胞中没有增加。Mirk激酶抑制升高了ROS水平，并通过组蛋白H2 AX磷酸化增加和S期检查点检测到DNA损伤。Mirk激酶抑制剂增加了凋亡蛋白PARP和半胱天冬酶3的裂解，并增加了吉西他滨和顺铂对肿瘤细胞的杀伤。这些影响的表型发生后Mirk耗尽，显示药物特异性。在先前的研究中，Mirk敲除或耗尽对正常组织没有可检测的影响，这表明Mirk激酶抑制剂可能对表达升高水平的Mirk激酶的癌细胞具有选择性作用。
A major problem in the treatment of cancer arises from quiescent cancer cells that are relatively insensitive to most chemotherapeutic drugs and radiation. Such residual cancer cells can cause tumor regrowth or recurrence when they re-enter the cell cycle. Earlier studies demonstrated that levels of the serine/theronine kinase Mirk/dyrk1B are elevated up to 10-fold in quiescent G0 tumor cells, that Mirk uses several mechanisms to block cell cycling, and that Mirk increases expression of antioxidant genes which lower ROS levels and increase quiescent cell viability. We now show that a novel small molecule Mirk kinase inhibitor blocked tumor cells from undergoing reversible arrest in a quiescent G0 state and enabled some cells to exit quiescence. The inhibitor increased cycling in Panc1, AsPc1 and SW620 cells that expressed Mirk, but not in HCT116 cells that did not. Mirk kinase inhibition elevated ROS levels and DNA damage detected by increased phosphorylation of the histone protein H2AX and by S phase checkpoints. The Mirk kinase inhibitor increased cleavage of the apoptotic proteins PARP and caspase 3, and increased tumor cell kill several-fold by gemcitabine and cisplatin. A phenocopy of these effects occurred following Mirk depletion, showing drug specificity. In prior studies Mirk knockout or depletion had no detectable effect on normal tissue, suggesting that the Mirk kinase inhibitor could have a selective effect on cancer cells expressing elevated levels of Mirk kinase.