The CDK4/6 Inhibitor PD0332991 Reverses Epithelial Dysplasia Associated with Abnormal Activation of the Cyclin-CDK-Rb Pathway
The CDK4/6 Inhibitor PD0332991 Reverses Epithelial Dysplasia Associated with Abnormal Activation of the Cyclin-CDK-Rb Pathway
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DOI：
10.1158/1940-6207.capr-11-0532-t
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发表时间：
2012-06-01
影响因子：
3.3
通讯作者：
Furth, Priscilla A.
中科院分区：
文献类型：
--
作者：
Cabrera, M. Carla;Diaz-Cruz, Edgar S.;Furth, Priscilla A.
正常生长控制的丧失是癌症进展的标志。因此，了解正常生长调节的早期机制和癌前病变期间发生的变化可能提供诊断和治疗重要性的见解。有助于阐明疾病进展机制的异型增生模型有助于突出潜在的预防目标。癌症预防治疗方案中的一个重要策略是减少增生和异型增生。这项研究确定了细胞周期相关蛋白细胞周期蛋白D1，细胞周期蛋白依赖性激酶（CDK）4，CDK 6和磷酸化视网膜母细胞瘤蛋白（pRb）的异常上调作为负责维持增殖和发育不良的机制，下调起始病毒癌蛋白猿猴病毒40（SV 40）T抗原。值得注意的是，成功逆转增生和异型增生并不需要p53。配体诱导的类维生素A X受体和过氧化物酶体增殖物激活受体γ激动剂的激活减弱细胞周期蛋白D1和CDK 6，但不CDK 4或磷酸化pRb的上调与有限的逆转增生和异型增生。PD 0332991是一种口服CDK 4/6抑制剂，能够阻止细胞周期蛋白D1和CDK 6以及CDK 4和磷酸化pRb的上调，这与增生和异型增生的更深刻逆转相关。总之，该研究将CDK 4和磷酸化pRb区分为靶向逆转增生和异型增生的化学预防方案的靶点。Cancer Prev Res; 5（6）; 810-21. (c)2012年AACR。
Loss of normal growth control is a hallmark of cancer progression. Therefore, understanding the early mechanisms of normal growth regulation and the changes that occur during preneoplasia may provide insights of both diagnostic and therapeutic importance. Models of dysplasia that help elucidate the mechanisms responsible for disease progression are useful in highlighting potential targets for prevention. An important strategy in cancer prevention treatment programs is to reduce hyperplasia and dysplasia. This study identified abnormal upregulation of cell cycle-related proteins cyclin D1, cyclin-dependent kinase (CDK) 4, CDK6, and phosphorylated retinoblastoma protein (pRb) as mechanisms responsible for maintenance of hyperplasia and dysplasia following downregulation of the initiating viral oncoprotein Simian virus 40 (SV40) T antigen. Significantly, p53 was not required for successful reversal of hyperplasia and dysplasia. Ligand-induced activation of retinoid X receptor and PPAR gamma agonists attenuated cyclin D1 and CDK6 but not CDK4 or phosphorylated pRb upregulation with limited reversal of hyperplasia and dysplasia. PD0332991, an orally available CDK4/6 inhibitor, was able to prevent upregulation of cyclin D1 and CDK6 as well as CDK4 and phosphorylated pRb and this correlated with a more profound reversal of hyperplasia and dysplasia. In summary, the study distinguished CDK4 and phosphorylated pRb as targets for chemoprevention regimens targeting reversal of hyperplasia and dysplasia. Cancer Prev Res; 5(6); 810-21. (c) 2012 AACR.