Abstract：
:Inhibition of the survival kinase Akt can trigger apoptosis, and also has been found to activate autophagy, which may confound tumor attack. In this study, we investigated regulatory mechanisms through which apoptosis and autophagy were modulated in tumor cells subjected to Akt inhibition by MK-2206, the first allosteric small molecule inhibitor of Akt to enter clinical development. In human glioma cells, Akt inhibition by MK-2206 or siRNA-mediated attenuation strongly activated autophagy, whereas silencing of eukaryotic elongation factor-2 (eEF-2) kinase, a protein synthesis regulator, blunted this autophagic response. Suppression of MK-2206-induced autophagy by eEF-2 silencing was accompanied by a promotion of apoptotic cell death. Similarly, siRNA-mediated inhibition of eEF-2 kinase potentiated the efficacy of MK-2206 against glioma cells. Together, these results showed that blunting autophagy and augmenting apoptosis by inhibition of eEF-2 kinase could modulate the sensitivity of glioma cells to Akt inhibition. Our findings suggest that targeting eEF-2 kinase may reinforce the antitumor efficacy of Akt inhibitors such as MK-2206.
journal_name
Cancer Resjournal_title
Cancer researchauthors
Cheng Y,Ren X,Zhang Y,Patel R,Sharma A,Wu H,Robertson GP,Yan L,Rubin E,Yang JMdoi
10.1158/0008-5472.CAN-10-2889subject
Has Abstractpub_date
2011-04-01 00:00:00pages
2654-63issue
7eissn
0008-5472issn
1538-7445pii
0008-5472.CAN-10-2889journal_volume
71pub_type
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