潜在的癌症治疗靶点:癌蛋白CIP2A

摘要

蛋白磷酸酶在细胞的生命活动中起着关键作用,其中蛋白磷酸酶2A(protein phosphatase 2A, PP2A)可抑制多个关键致癌信号通路的活性,是一种重要的肿瘤抑制因子.因此,抑制PP2A的活性是人体正常细胞转化为癌细胞的条件之一.PP2A的癌性抑制剂(cancerous inhibitor of protein phosphatase 2A, CIP2A)是恶性肿瘤细胞中 PP2A的内源性抑制剂,它的异常表达可导致 PP2A失活.多项研究已证实了CIP2A在促进肿瘤生长、抗凋亡和肿瘤衰老诱导疗法中的作用.值得注意的是,高水平的CIP2A预示着多种癌症患者的预后不良.癌蛋白MYC(PP2A去磷酸化调节的癌蛋白之一)第62位丝氨酸的磷酸化水平可指示CIP2A的致癌活性.CIP2A和MYC之间的正反馈通路提高了MYC在癌细胞中的活性.此外,CIP2A还可提高其他癌蛋白的磷酸化水平及其活性,包括E2F1、AKT和Mtorc1.然而,CIP2A对于正常小鼠的生长发育并不是必不可少的.这些研究结果表明,在癌细胞中靶向CIP2A进而重新激活PP2A不失是一种癌症靶向治疗的新策略.本文将对靶向CIP2A的肿瘤治疗方法及其可行性进行讨论.%Protein phosphatase plays a key role in cell life activity,in which protein phosphatase 2A (PP2A)is a very important member of the protein phosphatase family. And PP2A can inhibit the activity of multiple key carcino-genic signaling pathways,which is an important tumor suppressor. Protein phosphatase 2A (PP2A)complexes func-tion as tumor suppressors by inhibiting the activity of several critical oncogenic signaling pathways. Consequently,inhi-bition of the PP2A phosphatase activity is one of many prerequisites for the transformation of normal human cells into cancerous cells. The aberrant expression of cancerous inhibitor of protein phosphatase 2A (CIP2A),a recently identi-fied endogenous PP2A inhibitor in malignant cells,is one such mechanism. Various independent studies have validated CIP2A's role in promoting tumor growth and resistance to apoptosis and senescence-inducing therapies. Notably,high CIP2A expression predicts poor patient prognosis in several human cancer types. Among the oncogenic proteins de-phosphorylated by PP2A,the MYC oncoprotein,which is phosphorylated at serine 62,has surfaced as a marker for the oncogenic activity of CIP2A. The positive-feedback loop between CIP2A and MYC augments the activity of MYC in cancer cells. In addition,CIP2A promotes the phosphorylation and activity of additional oncoproteins,including E2 F1 ,AKT and mTORC1 . However ,CIP2 A is not essential for normal mouse growth and development . These findings indicate that CIP2 A is a novel anticancer target based on PP2 A reactivation and inhibition of the onco-genic activity of its downstream effectors . The potential approaches and feasibility of targeting CIP2 A are dis-cussed here.