Both Notch signaling and Akt-mTOR signaling pathway are involved in glioma cell proliferation and survival. Previous studies have shown that Notch-1 is overexpressed in many glioma cell lines and primary human gliomas. Blocking of Notch signaling pathway can induces glioma cell apoptosis and growth suppression. However, the underlying molecular mechanism is not clear. We report that activation of the Notch pathway by intracellular domain of human Notch-1 (NIC-1) strongly activates Akt and promotes U251 glioma cell proliferation. Knockdown of Notch-1 by RNA interference suppresses Akt activation, reduces glioma cell growth rate and induce cell apoptosis. Following Notch-1 suppression, phosphorylated Akt and its downstream effector mTOR were reduced. Knockdown of Notch-1 also involves down-regulation of anti-apoptotic protein MCL-1, in parallel with activation of apoptotic associate proteins PARP, caspase-9 and caspase-3. Our data demonstrate that Notch-1 can positively regulate Akt-mTOR pathways, which is associated with glioma cell proliferation and apoptosis. This also suggests a molecular mechanism for the inhibitory effect of Notch-1 RNA interference on glioma cell proliferation through Akt-mTOR signaling pathway.

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