Skp2 targeting suppresses tumorigenesis by Arf-p53-independent cellular senescence

摘要

Cellular senescence has been recently shown to have an important role in opposing tumour initiation and promotion. Senescence induced by oncogenes or by loss of tumour suppressor genes is thought to critically depend on induction of the p19~(Arf)-p53 pathway. The Skp2 E3-ubiquitin ligase can act as a proto-oncogene and its aberrant overexpression is frequently observed in human cancers. Here we show that although Skp2 inactivation on its own does not induce cellular senescence, aberrant proto-oncogenic signals as well as inactivation of tumour suppressor genes do trigger a potent, tumour-suppressive senescence response in mice and cells devoid of Skp2. Notably, Skp2 inactivation and oncogenic-stress-driven senescence neither elicit activation of the p19~(Arf)-p53 pathway nor DNA damage, but instead depend on Atf4, p27 and p21. We further demonstrate that genetic Skp2 inactivation evokes cellular senescence even in oncogenic conditions in which the p19~(Arf)-p53 response is impaired, whereas a Skp2-SCF complex inhibitor can trigger cellular senescence in p53/Pten-deficient cells and tumour regression in preclinical studies. Our findings therefore provide proof-of-principle evidence that pharmacological inhibition of Skp2 may represent a general approach for cancer prevention and therapy.%最新研究表明，细胞衰老(细胞周期停滞的rn种不可逆形式)在体外可阻止肿瘤生长。现在，rnHui-Kuan Lin等人识别出一个以前人们不知道rn的通道，它能驱动衰老，但不需要大多数已知rn衰老调控因子的参与，而是通过转录因子ATF6rn以及依赖于细胞周期蛋白的激酶抑制因子p27rn和p21来传递信号。这个通道是通过使原致癌rn基因Skp2失去活性而被发现的，但只能是在rn致癌信号作用的背景下进行。在药理上以Skp2rn复合物为目标，可通过诱导细胞衰老而限制肿rn瘤生成，说明这样的药物在癌症预防和治疗方rn面也许会有效。