Inhibition of CDK1 as a potential therapy for tumors over-expressing MYC
Inhibition of CDK1 as a potential therapy for tumors over-expressing MYC
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DOI：
10.1038/nm1606
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发表时间：
2007-07-01
期刊：
影响因子：
82.9
通讯作者：
Bishop, J. Michael
中科院分区：
文献类型：
--
作者：
Goga, Andrei;Yang, Dun;Bishop, J. Michael
肿瘤细胞具有异常的细胞周期，这可能使它们的增殖对细胞周期蛋白依赖性激酶(CDKs)的抑制特别敏感，CDKs是细胞周期进程的重要调节因子。我们研究了CDK1抑制在不同致癌信号背景下的作用。当用小分子CDK1抑制剂处理时，转化了MYC的细胞，而不是由一组其他激活的癌基因转化的细胞，迅速发生了凋亡。凋亡抑制蛋白BIRC5(Survivin)是一种已知的CDK1靶点，是过度表达MYC的细胞生存所必需的。抑制CDK1可迅速下调Survivin的表达，并诱导MYC依赖的细胞凋亡。CDK1抑制剂对依赖MYC的小鼠淋巴瘤和肝母细胞瘤的治疗减少了肿瘤的生长，延长了其生存时间。由于没有有效的小分子抑制剂选择性地靶向MYC通路，因此我们认为CDK1抑制可能在过度表达MYC的人类恶性肿瘤的治疗中有用。
Tumor cells have a dysregulated cell cycle that may render their proliferation especially sensitive to the inhibition of cyclin-dependent kinases (CDKs), important regulators of cell cycle progression. We examined the effects of CDK1 inhibition in the context of different oncogenic signals. Cells transformed with MYC, but not cells transformed by a panel of other activated oncogenes, rapidly underwent apoptosis when treated with small-molecule CDK1 inhibitors. The inhibitor of apoptosis protein BIRC5 (survivin), a known CDK1 target, is required for the survival of cells over-expressing MYC. Inhibition of CDK1 rapidly downregulates survivin expression and induces MYC-dependent apoptosis. CDK1 inhibitor treatment of MYC-dependent mouse lymphoma and hepatoblastoma tumors decreased tumor growth and prolonged their survival. As there are no effective small-molecule inhibitors that selectively target the MYC pathway, we propose that CDK1 inhibition might therefore be useful in the treatment of human malignancies that overexpress MYC.