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PLoS One. 2010 Mar 16;5(3):e9715. doi: 10.1371/journal.pone.0009715.

Cytoprotective effect of the elongation factor-2 kinase-mediated autophagy in breast cancer cells subjected to growth factor inhibition.

Author information

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.

Abstract

BACKGROUND:

Autophagy 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 Ca(2+)/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 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.

PMID:
20300520
PMCID:
PMC2838786
DOI:
10.1371/journal.pone.0009715
[Indexed for MEDLINE]
Free PMC Article

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