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Accession Number:
ADA516336
Title:
The Importance of Autophagy in Breast Cancer Development and Treatment
Descriptive Note:
Annual rept. 16 May 2007-15 May 2008
Corporate Author:
UNIVERSITY OF MEDICINE AND DENTISTRY OF NEW JERSEY NEW BRUNSWICK
Report Date:
2008-06-01
Pagination or Media Count:
17.0
Abstract:
In the current study, we tested the hypothesis that eEF-2 kinase plays a critical role in the ability of breast cancer cells to survive growth factornutrient deprivation. We found that eEF-2 kinase and autophagy were activated following starvation treatment in human breast cancer cells. Nutrient starvation also decreased mTOR activity, and reduced the incorporation rate of 35S-methionine, indicating protein synthesis was inhibited. Silencing of eEF-2 kinase by RNAi relieved the inhibition of protein synthesis, and resulted in a greater reduction of cellular ATP. EEF-2 kinase-targeted RNAi also blunted autophagic response of the tumor cells. Inhibition of autophagy by knockdown of eEF-2 kinase or autophagy-related gene Beclin-1 impeded cell growth in serumnutrient-deprived cultures and handicapped cell survival. These results indicate that in response to nutrientgrowth factor deprivation breast cancer cells activates eEF-2 kinase and autophagy to decrease protein synthesis and regenerate ATP, and that inhibition of eEF-2 kinase renders cells continue to elongate peptide, deplete ATP, and impairs cancer cell survival under metabolic stress. Furthermore, we determined whether inhibition of autophagy sensitized breast cancer cells to growth factor antagonists. Synergistic effect on cell growth inhibition was observed from combination of a small molecule EGFRErbB-2 inhibitor with an autophagy inhibitor 3-methyladenine combination index values at ED50 0.6279 and 0.7879, respectively. Inhibition of autophagy by knockdown of eEF-2 kinase or Beclin 1 sensitized breast cancer cells to the EGFRErbB-2 inhibitor and the mTOR inhibitor rapamycin. These results provide new evidence that activation of eEF-2 kinase and autophagy plays protective role for cancer cells under metabolic stress, and that targeting autophagic survival may represent a novel approach to sensitizing cancer cells to growth factor antagonists.
Distribution Statement:
APPROVED FOR PUBLIC RELEASE
