Increased activity of both CDK1 and CDK2 is necessary for the combinatorial activity of WEE1 inhibition and cytarabine.
Increased activity of both CDK1 and CDK2 is necessary for the combinatorial activity of WEE1 inhibition and cytarabine.
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DOI：
10.1016/j.leukres.2017.11.004
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发表时间：
2018-01
影响因子：
2.7
通讯作者：
Porter CC
中科院分区：
文献类型：
--
作者：
Garcia TB;Fosmire SP;Porter CC
抑制WEE1正在成为包括急性白血病在内的许多癌症的一种很有前途的化疗增敏策略。我们的实验室和其他人已经证明了WEE1的小分子抑制剂AZD1775使急性白血病细胞对阿糖胞苷敏感；然而，组合活性的机制仍然不清楚。因此，我们试图确定WEE1靶标CDK1和CDK2对AZD1775和阿糖胞苷组合活性的相对贡献。为此，我们在T-ALL细胞系中表达了抗WEE1的CDK1(CDK1-AF)和CDK2(CDK2-AF)。CDK1/2-AF联合表达可增强阿糖胞苷诱导的细胞增殖抑制、DNA损伤和细胞凋亡。此外，单独或联合抑制CDK1或CDK1和CDK2可降低AZD1775和阿糖胞苷的联合活性。因此，提高CDK1和CDK2的活性以响应WEE1抑制对于AZD1775和阿糖胞苷的组合活性是必要的。这表明WEE1在DNA损伤累积的细胞中的作用超出了CDK1和G2/M检查点的调控范围，并强调了WEE1在细胞周期中调节进展的重要性。
Inhibition of WEE1 is emerging as a promising chemosensitization strategy in many cancers including acute leukemia. Our lab and others have demonstrated that a small-molecule inhibitor of WEE1, AZD1775, sensitizes acute leukemia cells to cytarabine; however, a mechanism of combinatorial activity has remained elusive. Thus, we sought to determine the relative contribution of WEE1 targets CDK1 and CDK2 to the combinatorial activity of AZD1775 and cytarabine. To accomplish this, we expressed “WEE1 resistant” CDK1 (CDK1-AF) and CDK2 (CDK2-AF) constructs in a T-ALL cell line. Expression of CDK1/2-AF together, but neither alone, enhanced the anti-proliferative effects, DNA damage and apoptosis induced by cytarabine. Furthermore, pharmacologic inhibition of CDK1 alone or CDK1 and CDK2 together reduced the combinatorial activity of AZD1775 and cytarabine. Thus, increased activity of both CDK1 and CDK2 in response to WEE1 inhibition is necessary for the combinatorial activity of AZD1775 and cytarabine. This suggests the role of WEE1 in cells with accumulated DNA damage extends beyond regulation of CDK1 and the G2/M checkpoint and highlights the importance of WEE1 in mediating progression through the cell cycle.
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DOI：
10.1083/jcb.134.4.963
发表时间：
1996-08
期刊：
The Journal of cell biology
影响因子：
--
作者：
Jin P;Gu Y;Morgan DO
通讯作者：
Morgan DO
影响因子：
16.8
作者：
Mahajan K;Fang B;Koomen JM;Mahajan NP
通讯作者：
Mahajan NP
影响因子：
8
作者：
Krajewska, M.;Heijink, A. M.;van Vugt, M. A. T. M.
通讯作者：
van Vugt, M. A. T. M.
影响因子：
5.8
作者：
Chu, Rong;Terrano, David T.;Chambers, Timothy C.
通讯作者：
Chambers, Timothy C.
影响因子：
3.4
作者：
Johnston, CJ;Williams, JP;Finkelstein, JN
通讯作者：
Finkelstein, JN