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抑癌因子ATM也可促癌症

新药编辑:新特药 更新时间:2015-04-20

2015年4月20日讯 /tumor.net.cn/ -- 近日,国际学术期刊nature communication在线发表了意大利学家的一项研究成果,他们发现DNA损伤修复途径关键激酶ATM除具有肿瘤抑制作用,还可通过HER2促进癌症发生。这项研究发现作为抑癌因子的ATM也可发挥促癌作用,具有一定研究意义。

之前研究发现ATM激酶对于维持基因组稳定具有重要功能,是细胞内一个重要的肿瘤抑制因子。但是有结果显示ATM可参与癌细胞内多条信号途径,表明ATM在癌症中的作用可能具有多面性。

在该项研究中,研究人员发现ATM的表达及其活性发挥对于促进HER2依赖性的癌症发生具有重要作用,并且这种促癌作用在体内和体外实验中均得到了验证。研究人员揭示了ATM激活与HER2阳性乳腺癌病人复发时间缩短之间的关系。

通过进一步实验发现,ATM能够通过促进HER2与分子伴侣HSP90形成复合物,抑制HER2泛素化发生,阻断其降解,从而实现对HER2蛋白稳定性的调节。ATM增强了HER2的蛋白稳定,能够维持HER2下游AKT的激活,可能调节了癌细胞对癌症治疗的应答,这表明ATM的活性水平可能对于HER2阳性肿瘤的治疗和预后具有重要提示作用。

这项研究发现了ATM的促肿瘤发生潜能,修正了人们以往对于ATM单纯作为肿瘤抑制因子发挥经典功能的认识,具有一定研究意义。(tumor.net.cn)

ATM kinase sustains HER2 tumorigenicity in breast cancer

Venturina Stagni,Isabella Manni,Veronica Oropallo,Marcella Mottolese,Anna Di Benedetto,Giulia Piaggio,Rita Falcioni,Danilo Giaccari,Selene Di Carlo,Francesca Sperati,Maria Teresa Cencioni & Daniela Barilà

ATM kinase preserves genomic stability by acting as a tumour suppressor. However, its identification as a component of several signalling networks suggests a dualism for ATM in cancer. Here we report that ATM expression and activity promotes HER2-dependent tumorigenicity in vitroand in vivo. We reveal a correlation between ATM activation and the reduced time to recurrence in patients diagnosed with invasive HER2-positive breast cancer. Furthermore, we identify ATM as a novel modulator of HER2 protein stability that acts by promoting a complex of HER2 with the chaperone HSP90, therefore preventing HER2 ubiquitination and degradation. As a consequence, ATM sustains AKT activation downstream of HER2 and may modulate the response to therapeutic approaches, suggesting that the status of ATM activity may be informative for the treatment and prognosis of HER2-positive tumours. Our findings provide evidence for ATM's tumorigenic potential revising the canonical role of ATM as a pure tumour suppressor.

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