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Autophagy In Life and Disease

Autophagy In Life and Disease. By: LaShanale Wallace. Overview. Introduction: What is Autophagy? Objective Specific examples Conclusion. What is autophagy…. A vital cellular process by which intracellular components are degraded within the lysosome

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Autophagy In Life and Disease

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  1. Autophagy In Life and Disease By: LaShanale Wallace

  2. Overview • Introduction: What is Autophagy? • Objective • Specific examples • Conclusion

  3. What is autophagy… • A vital cellular process by which intracellular components are degraded within the lysosome • An essential for survival, differentiation, development, and homeostasis

  4. Primary fuNCTION • Is to ensure cell survival through unfavorable situations ex…. • Nutrient absence • Growth factor withdraw • Abundant amount of toxic proteins • Defected organells

  5. Objective • The Roles of Autophagy in life and disease

  6. Autophagy in Life and disease

  7. Literature Review • Focusing on the dual roles of autophagy • Specific examples are… • Its role as cytoprotective autophagy • Its role in skeletal muscle and aging • And its role in pancreatic cancer

  8. Autophagic degradation of active caspase-8: a CROSS TALK MECHANISM BETWEEN AUTOPHAGY AND APOPTOSIS • Purpose • Investigate expression pattern and sublocalization of caspase 8 in TRAIL mediated autophagy • Expression of caspase 8 in shift from autophagy to apoptosis • Materials • HCT colon carcinoma cells treated with TRAIL

  9. Method Quantitative image cytometry, Confocal microscopy assay. Immunoblot Inhibition of autophagy induces caspase 8 activity Cleaved caspase 8 localizes to autophagosome, inhibiting apoptosis Results

  10. Conclusion • This study provides evidence for regulation of caspase 8 activity through autophagy • Capase 8 provides a cross talk mechanism between autophagy and apoptosis

  11. Skeletal muscle autophagy and apoptosis during aging: Effects of calorie restriction and life long exercise • Purpose • Does autophagy in skeletal muscle change with age? • Does exercise and calorie restriction have an effect on autophagy? • Materials • Male Fisher Rats • Ad libthium diet • Four groups: Y,O, OCR, and OCREX • Fast twitch muscle tissue

  12. Results Autophagy decreases with age. Calorie restriction increased autophagy response Exercise had no significant effect Methods and Results

  13. Conclusion • Age is associated with lower levels of autophagy. This leads to increased cellular damage and apoptosis causing muscle loss. • Mild calorie restricted diets increased autophagy in older rats, protecting muscle from cell damage and death

  14. Pancreatic cancers require autophagy for tumor growth • Purpose • Demonstrate that pancreatic cancers are dependent on autophagy for growth • Pancreatic tumor cells are sensitive to autophagy inhibition

  15. Materials meTHODS • Pancreatic ductal adenocarcinoma cells(PDAC) • Control cell lines MCF7, H460, AND HPDE • GFP-LC3 assay • Chloroquine inhibitor • Assay determined degree of autophagy • Immunochemistry monitored LC3 expression during tumor progression • CQ Treatment

  16. Results • PDAC has high levels of basal autophagy • Autophagy is upregulated during tumor progression • PDAC is sensitive to CQ treatment • PDAC Mice treated with CQ live longer

  17. CONCLUSION • Since PDAC is dependent on autophagy, this provides a potential target for therapeutic intervention • Since chloroquine is already used as a anti-malaria therapeutic, clinical trials using drugs targeting autophagy inhibition are strongly suggested for pancreatic cancer

  18. Overall SUMMARY • Functions of autophagy can be beneficial are harmful • Its role to promote cell survival…. • Is beneficial in life processes such as aging • Harmful in diseases like pancreatic cancer • With knowledge researchers can create therapeutics and either inhibit or increase autophagy pathways for more favorable outcomes.

  19. Acknowledgements • Dr. Muganda • MARC Program • Dr. White • Mrs. Petty • Mrs. Sindy Martin

  20. References • Wohlgemuth, S. E., Seo, A. Y., Marzetti, E., Lees, H. A., and Leeuwenburgh, C. Skeletal muscle autophagy and apoptosis during aging: effects of calorie restriction and life-long exercise. Experimental Gerontology 2010; 45: 138-148. • Young M, T. Y., Khan O, Park S, Hori T, Yun J, Amin S, Hu C, Zhang J, Kester M, and Wang H. Autophagosomal membrane serves as a platform for an intracellular death-inducing signaling complex (iDISC)-mediated caspase-8 activation and apoptosis. The Journal of Biological Chemistry. 2012; 287: 12455-12468. • Rosenfeldt MT, Ryan KM. The multiple roles of autophagy in cancer. Carcinogenesis. 2011; 32(7): 955-963. • http://tp-apg.genes.nig.ac.jp/autophagy/ • http://www.wormbook.org/chapters/www_autophagy/autophagy.html • http://www.invitrogen.com/site/us/en/home/References/Molecular-Probes-The-Handbook/Assays-for-Cell-Viability-Proliferation-and-Function/Assays-for-Apoptosis.html#head7 • http://beaker.sanfordburnham.org/2011/09/autophagy-101/

  21. Questions??????????

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