Abstract | BACKGROUND: METHODOLOGY/PRINCIPAL FINDINGS: We 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/SIGNIFICANCE: The 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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Authors | Yan Cheng, Huaijun Li, Xingcong Ren, Tingkuang Niu, William N Hait, Jinming Yang |
Journal | PloS one
(PLoS One)
Vol. 5
Issue 3
Pg. e9715
(Mar 16 2010)
ISSN: 1932-6203 [Electronic] United States |
PMID | 20300520
(Publication Type: Journal Article, Research Support, N.I.H., Extramural)
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Chemical References |
- Antibodies, Monoclonal
- Antibodies, Monoclonal, Humanized
- Antineoplastic Agents
- Intercellular Signaling Peptides and Proteins
- Quinazolines
- Lapatinib
- Elongation Factor 2 Kinase
- Adenylate Kinase
- Trastuzumab
- Gefitinib
- Calcium
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Topics |
- Adenylate Kinase
(metabolism)
- Antibodies, Monoclonal
(pharmacology)
- Antibodies, Monoclonal, Humanized
- Antineoplastic Agents
(pharmacology)
- Autophagy
- Breast Neoplasms
(metabolism)
- Calcium
(metabolism)
- Cell Line, Tumor
- Elongation Factor 2 Kinase
(genetics, physiology)
- Female
- Gefitinib
- Gene Expression Regulation, Neoplastic
- Humans
- Intercellular Signaling Peptides and Proteins
(metabolism)
- Lapatinib
- Quinazolines
(pharmacology)
- Signal Transduction
- Trastuzumab
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