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

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.

• Authors: Yan Cheng, Xingcong Ren, Yi Zhang, Rajesh Patel, Arati Sharma, Hao Wu, Gavin P Robertson, Li Yan, Eric Rubin, Jin-Ming Yang
• Journal: Cancer research (Cancer Res) Vol. 71 Issue 7 Pg. 2654-63 (Apr 01 2011) ISSN: 1538-7445 [Electronic] United States
• PMID: 21307130 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Heterocyclic Compounds, 3-Ring
• MK 2206
• Protein Kinase Inhibitors
• RNA, Small Interfering
• Reactive Oxygen Species
• Tuberous Sclerosis Complex 2 Protein
• Tumor Suppressor Proteins
• MTOR protein, human
• EEF2K protein, human
• Proto-Oncogene Proteins c-akt
• Ribosomal Protein S6 Kinases
• TOR Serine-Threonine Kinases
• Elongation Factor 2 Kinase

Topics

• Animals
• Apoptosis (drug effects, physiology)
• Autophagy (drug effects, physiology)
• Cell Line, Tumor
• Elongation Factor 2 Kinase (metabolism)
• Female
• Glioblastoma (drug therapy, enzymology, pathology)
• Heterocyclic Compounds, 3-Ring (pharmacology)
• Humans
• Mice
• Mice, Nude
• Mitochondria (metabolism)
• Protein Kinase Inhibitors (pharmacology)
• Proto-Oncogene Proteins c-akt (antagonists & inhibitors, metabolism)
• RNA Interference
• RNA, Small Interfering (administration & dosage, genetics)
• Reactive Oxygen Species (metabolism)
• Ribosomal Protein S6 Kinases (metabolism)
• TOR Serine-Threonine Kinases (metabolism)
• Transfection
• Tuberous Sclerosis Complex 2 Protein
• Tumor Suppressor Proteins (metabolism)