Activation of nuclear PTEN by inhibition of Notch signaling induces G2/M cell cycle arrest in gastric cancer
Activation of nuclear PTEN by inhibition of Notch signaling induces G2/M cell cycle arrest in gastric cancer
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DOI：
10.1038/onc.2015.80
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发表时间：
2016-01-14
期刊：
影响因子：
8
通讯作者：
Chun, K-H
中科院分区：
文献类型：
--
作者：
Kim, S-J;Lee, H-W;Chun, K-H
目前还没有检测到PTEN的突变，但它作为肿瘤抑制因子的功能在许多癌症中都是失活的。在这项研究中，我们确定了激活的Notch信号通过磷酸化使PTEN失活，从而促进了胃肿瘤的发生。小干扰RNA或分泌酶抑制剂(GSI)抑制缺口诱导胃癌细胞有丝分裂停滞和凋亡。缺口抑制诱导PTEN C-末端结构域去磷酸化，导致PTEN核定位。过表达激活的Notch1诱导PTEN的磷酸化并逆转GSI诱导的有丝分裂停滞。去磷酸化的核PTEN通过与细胞周期蛋白B1-CDK1复合体相互作用，导致细胞周期蛋白B1-CDK1复合体的前中期停滞，导致它们在细胞核内积聚，从而导致细胞凋亡。我们发现，在胃癌患者的恶性肿瘤组织中，Notch1的高表达水平与低生存率之间存在相关性，类似地，核PTEN表达的降低与恶性肿瘤的TNM分期增加之间也存在相关性。在异种移植小鼠中，Notch1缺失的胃肿瘤的生长受到显著抑制，此外，PTEN缺失恢复了与对照肿瘤相似的生长。我们还证明，GSI和化疗药物的联合治疗显著减少了小鼠原位移植的胃肿瘤，而没有明显的毒性。总体而言，我们的发现表明，抑制Notch信号可以作为PTEN的激活剂，使其成为胃癌治疗的潜在靶点。
Mutation in PTEN has not yet been detected, but its function as a tumor suppressor is inactivated in many cancers. In this study we determined that, activated Notch signaling disables PTEN by phosphorylation and thereby contributes to gastric tumorigenesis. Notch inhibition by small interfering RNA or.-secretase inhibitor (GSI) induced mitotic arrest and apoptosis in gastric cancer cells. Notch inhibition induced dephosphorylation in the C-terminal domain of PTEN, which led to PTEN nuclear localization. Overexpression of activated Notch1-induced phosphorylation of PTEN and reversed GSI-induced mitotic arrest. Dephosphorylated nuclear PTEN caused prometaphase arrest by interaction with the cyclin B1-CDK1 complex, resulting in their accumulation in the nucleus and subsequent apoptosis. We found a correlation between high expression levels of Notch1 and low survival rates and, similarly, between reduced nuclear PTEN expression and increasing the TNM classification of malignant tumours stages in malignant tissues from gastric cancer patients. The growth of Notch1-depleted gastric tumors was significantly retarded in xenografted mice, and in addition, PTEN deletion restored growth similar to control tumors. We also demonstrated that combination treatment with GSI and chemotherapeutic agents significantly reduced the orthotopically transplanted gastric tumors in mice without noticeable toxicity. Overall, our findings suggest that inhibition of Notch signaling can be employed as a PTEN activator, making it a potential target for gastric cancer therapy.