title: Integrated regulation of autophagy and apoptosis by EEF2K controls cellular fate and modulates the efficacy of curcumin and velcade against tumor cells.
abstract: Endoplasmic reticulum (ER) stress induces both autophagy and apoptosis yet the molecular mechanisms and pathways underlying the regulation of these two cellular processes in cells undergoing ER stress remain less clear. We report here that eukaryotic elongation factor-2 kinase (EEF2K) is a critical controller of the ER stress-induced autophagy and apoptosis in tumor cells. DDIT4, a stress-induced protein, was required for transducing the signal for activation of EEF2K under ER stress. We further showed that phosphorylation of EEF2K at Ser398 was essential for induction of autophagy, while phosphorylation of the kinase at Ser366 and Ser78 exerted an inhibitory effect on autophagy. Suppression of the ER stress-activated autophagy via silencing of EEF2K aggravated ER stress and promoted apoptotic cell death in tumor cells. Moreover, inhibiting EEF2K by either RNAi or NH125, a small molecule inhibitor of the enzyme, rendered tumor cells more sensitive to curcumin and velcade, two anticancer agents that possess ER stress-inducing action. Our study indicated that the DDIT4-EEF2K pathway was essential for inducing autophagy and for determining the fate of tumor cells under ER stress, and suggested that inhibiting the EEF2K-mediated autophagy can deteriorate ER stress and lead to a greater apoptotic response, thereby potentiating the efficacy of the ER stress-inducing agents against cancer.
authors.affiliation: Department of Pharmacology, Penn State Hershey Cancer Institute, Pennsylvania State University College of Medicine and Milton S. Hershey Medical Center, Hershey, PA, USA. yxc24@psu.edu
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: Yu
authors.initials: Y
authors.lastname: Shan
authors.forename: Kathryn J
authors.initials: KJ
authors.lastname: Huber-Keener
authors.forename: Li
authors.initials: L
authors.lastname: Zhang
authors.forename: Scot R
authors.initials: SR
authors.lastname: Kimball
authors.forename: Harold
authors.initials: H
authors.lastname: Harvey
authors.forename: Leonard S
authors.initials: LS
authors.lastname: Jefferson
authors.forename: Jin-Ming
authors.initials: JM
authors.lastname: Yang
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D001343:Autophagy / Q000187:drug effects*; D001897:Boronic Acids / Q000494:pharmacology*; D000069286:Bortezomib; D045744:Cell Line, Tumor; D019070:Cell Lineage / Q000187:drug effects*; D003474:Curcumin / Q000494:pharmacology*; D054736:Elongation Factor 2 Kinase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D020868:Gene Silencing / Q000187:drug effects; D006801:Humans; D008954:Models, Biological; D010766:Phosphorylation / Q000187:drug effects; D010768:Phosphoserine / Q000378:metabolism; D011719:Pyrazines / Q000494:pharmacology*; D019284:Thapsigargin / Q000494:pharmacology; D014157:Transcription Factors / Q000378:metabolism; D014415:Tunicamycin / Q000494:pharmacology
chemical_list: D001897:Boronic Acids; C469991:DDIT4 protein, human; D011719:Pyrazines; D014157:Transcription Factors; D014415:Tunicamycin; D010768:Phosphoserine; D019284:Thapsigargin; D000069286:Bortezomib; D054736:Elongation Factor 2 Kinase; D003474:Curcumin