title: 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.affiliation: Department of Pharmacology and The Penn State Hershey Cancer Institute, The Pennsylvania State University College of Medicine, Hershey, Pennsylvania, USA.
authors.forename: Yan
authors.initials: Y
authors.lastname: Cheng
authors.forename: Xingcong
authors.initials: X
authors.lastname: Ren
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhang
authors.forename: Rajesh
authors.initials: R
authors.lastname: Patel
authors.forename: Arati
authors.initials: A
authors.lastname: Sharma
authors.forename: Hao
authors.initials: H
authors.lastname: Wu
authors.forename: Gavin P
authors.initials: GP
authors.lastname: Robertson
authors.forename: Li
authors.initials: L
authors.lastname: Yan
authors.forename: Eric
authors.initials: E
authors.lastname: Rubin
authors.forename: Jin-Ming
authors.initials: JM
authors.lastname: Yang
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D001343:Autophagy / Q000187:drug effects / Q000502:physiology*; D045744:Cell Line, Tumor; D054736:Elongation Factor 2 Kinase / Q000378:metabolism*; D005260:Female; D005909:Glioblastoma / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology*; D006575:Heterocyclic Compounds, 3-Ring / Q000494:pharmacology*; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D008928:Mitochondria / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors* / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000008:administration & dosage / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism; D019893:Ribosomal Protein S6 Kinases / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D014162:Transfection; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins / Q000378:metabolism
chemical_list: D006575:Heterocyclic Compounds, 3-Ring; C548887:MK 2206; D047428:Protein Kinase Inhibitors; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins; C546842:MTOR protein, human; C517689:EEF2K protein, human; D051057:Proto-Oncogene Proteins c-akt; D019893:Ribosomal Protein S6 Kinases; D058570:TOR Serine-Threonine Kinases; D054736:Elongation Factor 2 Kinase