Zalzali Hasan, Nasr Bilal, Harajly Mohamad, Basma Hussein, Ghamloush Farah, Ghayad Sandra, Ghanem Noël, Evan Gerard I, Saab Raya
Department of Pediatric and Adolescent Medicine, American University of Beirut, Beirut, Lebanon.
Department of Biology, American University of Beirut, Beirut, Lebanon.
Mol Cancer Res. 2015 Jan;13(1):29-40. doi: 10.1158/1541-7786.MCR-14-0163. Epub 2014 Aug 22.
Cellular senescence, a form of cell-cycle arrest, is a tumor-suppressor mechanism triggered by multiple tumor-promoting insults, including oncogenic stress and DNA damage. The role of cyclin-dependent kinase 2 (CDK2) regulation has been evaluated in models of replicative senescence, but little is known regarding its role in other senescence settings. Using in vitro and in vivo models of DNA damage-and oncogene-induced cellular senescence, it was determined that activation of the tumor-suppressor protein p53 (TP53) resulted in repression of the CDK2 transcript that was dependent on intact RB. Ectopic CDK2 expression was sufficient to bypass p53-dependent senescence, and CDK2-specific inhibition, either pharmacologically (CVT313) or by use of a dominant-negative CDK2, was sufficient to induce early senescence. Pharmacologic inhibition of CDK2 in an in vivo model of pineal tumor decreased proliferation and promoted early senescence, and it also decreased tumor penetrance and prolonged time to tumor formation in animals lacking p53. In conclusion, for both oncogene- and DNA damage-induced cellular senescence, CDK2 transcript and protein are decreased in a p53- and RB-dependent manner, and this repression is necessary for cell-cycle exit during senescence.
These data show that CDK2 inhibition may be useful for cancer prevention in premalignant hyperproliferative lesions, as well as established tumors.
细胞衰老，一种细胞周期停滞的形式，是一种由多种促肿瘤损伤触发的肿瘤抑制机制，这些损伤包括致癌应激和DNA损伤。细胞周期蛋白依赖性激酶2（CDK2）调节在复制性衰老模型中的作用已得到评估，但对于其在其他衰老情况下的作用知之甚少。利用DNA损伤和癌基因诱导的细胞衰老的体外和体内模型，确定肿瘤抑制蛋白p53（TP53）的激活导致CDK2转录本的抑制，这依赖于完整的RB。异位表达CDK2足以绕过p53依赖的衰老，而CDK2特异性抑制，无论是通过药理学方法（CVT313）还是使用显性负性CDK2，都足以诱导早期衰老。在松果体肿瘤的体内模型中，对CDK2进行药理学抑制可降低增殖并促进早期衰老，在缺乏p53的动物中，还可降低肿瘤发生率并延长肿瘤形成时间。总之，对于癌基因和DNA损伤诱导的细胞衰老，CDK2转录本和蛋白以p53和RB依赖的方式减少，这种抑制对于衰老过程中的细胞周期退出是必要的。
这些数据表明，抑制CDK2可能对癌前过度增殖性病变以及已形成的肿瘤的癌症预防有用。
