eEF-2 kinase dictates cross-talk between autophagy and apoptosis induced by Akt inhibition, thereby modulating cytotoxicity of novel Akt inhibitor MK-2206

Yan Cheng, Xingcong Ren, Yi Zhang, Rajesh Patel, Arati Sharma, Hao Wu, Gavin P. Robertson, Li Yan, Eric Rubin, Jin Ming Yang

Research output: Contribution to journalArticle

96 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)2654-2663
Number of pages10
JournalCancer Research
Volume71
Issue number7
DOIs
StatePublished - Apr 1 2011

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

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