Cytoprotective Effect of the Elongation Factor-2 Kinase-Mediated Autophagy in Breast Cancer Cells Subjected to Growth Factor Inhibition |
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Authors: | Yan Cheng Huaijun Li Xingcong Ren Tingkuang Niu William N. Hait Jinming Yang |
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Affiliation: | 1. Department of Pharmacology and The Penn State Cancer Institute, The Pennsylvania State University College of Medicine, and Milton S. Hershey Medical Center, Hershey, Pennsylvania, United States of America.; 2. Department of Pharmacology, School of Medicine, Soochow University, Suzhou, China.; 3. OrthoBiotech Research and Development, Raritan, New Jersey, United States of America.;Roswell Park Cancer Institute, United States of America |
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Abstract: | BackgroundAutophagy is a highly conserved and regulated cellular process employed by living cells to degrade proteins and organelles as a response to metabolic stress. We have previously reported that eukaryotic elongation factor-2 kinase (eEF-2 kinase, also known as Ca2+/calmodulin-dependent protein kinase III) can positively modulate autophagy and negatively regulate protein synthesis. The purpose of the current study was to determine the role of the eEF-2 kinase-regulated autophagy in the response of breast cancer cells to inhibitors of growth factor signaling.Methodology/Principal FindingsWe found that nutrient depletion or growth factor inhibitors activated autophagy in human breast cancer cells, and the increased activity of autophagy was associated with a decrease in cellular ATP and an increase in activities of AMP kinase and eEF-2 kinase. Silencing of eEF-2 kinase relieved the inhibition of protein synthesis, led to a greater reduction of cellular ATP, and blunted autophagic response. We further showed that suppression of eEF-2 kinase-regulated autophagy impeded cell growth in serum/nutrient-deprived cultures and handicapped cell survival, and enhanced the efficacy of the growth factor inhibitors such as trastuzumab, gefitinib, and lapatinib.Conclusion/SignificanceThe results of this study provide new evidence that activation of eEF-2 kinase-mediated autophagy plays a protective role for cancer cells under metabolic stress conditions, and that targeting autophagic survival may represent a novel approach to enhancing the effectiveness of growth factor inhibitors. |
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