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

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.

• 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)

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

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