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The Importance of Autophagy in Breast Cancer Development and Treatment

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  • Title:
    The Importance of Autophagy in Breast Cancer Development and Treatment
  • Author: Hait, William ; Yang, Jin-Ming
  • Contributor: University Of Medicine And Dentistry Of NEW Jersey Newark (Corporate Author)
  • Subjects: Genetic Engineering and Molecular Biology ; Medicine and Medical Research ; Inhibition ; Cells(Biology) ; Breast Cancer ; Phosphorus Transferases ; Depletion ; Elongation ; Deprivation ; Adenosine Phosphates ; Autophagy ; Elongation Factor-2 Kinase ; Growth Factor ; Protein Synthesis
  • Language: English
  • Description: Autophagy is an evolutionally conserved process employed by cells to degrade proteins and organelles in response to metabolic stress. Cells can recycle amino acids, fatty acids and nucleotides for macromolecular biosynthesis and ATP generation, and by sequestering damaged organelles can prevent the release or accumulation of toxic substances. We described elongation factor-2 kinase (eEF-2 kinase) as a structurally and functionally unique enzyme that is activated by starvation and phosphorylates and inactivates eEF-2, thereby terminating peptide chain elongation. Since protein synthesis is a major energy-consuming process, decreasing protein elongation by activating eEF-2 kinase could be an energy-saving survival strategy. We now test the hypothesis that eEF-2 kinase plays a critical role in the ability of cancer cells to survive oxygen and nutrient deprivation. MCF-7 human breast cancer cells were transfected with a GFP-tagged LC3 expression vector to track the formation of autophagosomes. Autophagy was induced by nutrient/growth factor deprivation as manifested by autophagosome formation in GFP-LC3-transfected MCF-7 cells. Treatment with a potent and specific inhibitor of eEF-2 kinase, NH125 inhibited autophagy as indicated by a reduction in autophagosome formation. In either transient or stable MCF-7 transfectants, NH125 was 10-times more potent and more effective than 3-methyladenine, a known autophagy inhibitor. To determine the effects of blocking autophagy via inhibition of eEF-2 kinase on cellular energetics, we studied the rate and amount of ATP depletion in NH125- and vehicle-treated MCF-7 transfectants. Following nutrient deprivation, inhibition of eEF-2 kinase by NH125 resulted in a greater and more rapid reduction of cellular ATP as compared to vehicle treatment. The original document contains color images.

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