Opposite Effects of Notch-1 and Notch-2 on Mesothelioma Cell Survival under Hypoxia Are Exerted through the Akt Pathway
Opposite Effects of Notch-1 and Notch-2 on Mesothelioma Cell Survival under Hypoxia Are Exerted through the Akt Pathway
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DOI：
10.1158/0008-5472.can-08-0969
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发表时间：
2008-12-01
期刊：
影响因子：
11.2
通讯作者：
Bocchetta, Maurizio
中科院分区：
文献类型：
--
作者：
Graziani, Irene;Eliasz, Sandra;Bocchetta, Maurizio
恶性间皮瘤(MM)是一种位于肺、心脏和肠道内层的癌症，已知对化疗的反应很差。在这里，我们显示恶性间皮细胞与正常的人间皮细胞相比，Notch信号通路升高。我们研究了在常氧和低氧条件下，Notch在MM中的作用，后者最好地概括了MM的微环境。Notch通路的遗传和化学调控表明，MM细胞依赖于Notch信号。更具体地说，这种信号是Notch-1依赖的，因为它对磷酸酶和张力蛋白同源物(PTEN)的负转录调节导致了生存的磷脂酰肌醇3-激酶(PI3K)/Akt/哺乳动物雷帕霉素靶标(MTOR)信号通路的激活。我们的研究还提供了证据表明，虽然Notch-1在恶性环境中升高，但Notch-2在恶性环境中降低。这两种Notch亚型的差异表达有利于癌细胞的存活，因为Notch-2的重新表达对MM细胞是有毒的。Notch-2对MM细胞的毒性机制与Notch-1相反，因为它是PTEN正转录调节和抑制PI3K/Akt/mTor信号通路的结果。这些结果为了解Notch在多发性骨髓瘤中的作用提供了新的见解，并表明Notch途径抑制剂可能在这种致命疾病的治疗中有用。[癌症资源2008；68(23)：9678-85]
Malignant mesothelioma (MM) is a cancer of the lining of the lungs, heart, and intestine and is known to respond poorly to chemotherapy. Here we show that malignant mesothelial cells have an elevated Notch signaling pathway compared with normal human mesothelial cells. We studied the role of Notch in MM under normoxic and hypoxic conditions, the latter condition best recapitulating the MM microenvironment. Genetic and chemical modulation of the Notch pathway indicated that MM cells are dependent on Notch signaling. More specifically, this signaling was Notch-1 dependent as the result of its negative transcriptional regulation on phosphatase and tensin homologue (PTEN), which led to activation of the prosurvival phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) signaling pathway. Our study also provides evidence that whereas Notch-1 is elevated in the malignant setting, Notch-2 is diminished. This differential expression of the two Notch isoforms benefits cancer cell survival because reexpression of Notch-2 was toxic to MM cells. The mechanism of Notch-2 toxicity to MM cells countered that of Notch-1, as it was the result of positive transcriptional regulation of PTEN and inhibition of the PI3K/Akt/mTOR signaling pathway. These results provide new insight into the role of Notch in MM and suggest that Notch pathway inhibitors may be useful in the treatment of this deadly disease. [Cancer Res 2008;68(23):9678-85]