Autophagy in cancer and disease
Fine tuning of cellular microenvironment
Chieh-Huei Wang, PhD
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Autophagy
www.genetex.comAutophagy: a basic cellular process in eukaryotes Phagy = eating/lysosomal degradation
Autophagy = self-eating
Mechanism of breakdown of cytoplasm within the lysosome
1963
Underlying Mechanisms of Autophagy
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Autophagy
Toxicological Sciences 119(1). 3-19, 2011
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Autophagy
Types of autophagy
GTX111150A GTX101144A GTX111069A GTX19136
GTX103214A GTX111812A GTX63319 GTX30881 GTX30729 GTX13524
The molecular machinery of autophagy
GTX128166 GTX119950 GTX120523
GTX107572 GTX129528 GTX107893 GTX63391 GTX25451
GTX113039 GTX60413 GTX113040 GTX61619 GTX37770 GTX16998
GTX116246A GTX116247C
GTX128064 GTX111476 GTX64029
GTX38837 GTX81221
GTX123970 GTX122766 ZF127215
GTX85183 GTX106501C
GTX107387 GTX129093 GTX129094
GTX45326
GTX128167 GTX64052 GTX44983 GTX44982 GTX122101
GTX102322 GTX62918 GTX124451 GTX62952
GTX116202 GTX116203 GTX60231 GTX102006
GTX63779 GTX15858 GTX31026 GTX30993 GTX10272
GTX71799 GTX78001 GTX78003 GTX128427 GTX62510 GTX63217 GTX117402 GTX85184
GTX102137 GTX13523 GTX19294 GTX62434 GTX42501 GTX80229 GTX42500 GTX43215 GTX44016 GTX40623
ZF125056 GTX63882 GTX109102 GTX106779 GTX117740 GTX129111 GTX103171 GTX108924
GTX124181 GTX629815 GTX629816 GTX629817 GTX62935 GTX62939 GTX42707 GTX42708 GTX42709 GTX42710 GTX59642
GTX102361 GTX113309 GTX48585 GTX48586 GTX48588 GTX48583 GTX62601 GTX48584 GTX62913 GTX48587 GTX88573 GTX59667 GTX19130
GTX113613 GTX61647 GTX63489
GTX106114
GTX104387 GTX115678 GTX115677
GTX129488 GTX106006 GTX88462 GTX85759 GTX62753 GTX87155 GTX87767
GTX60245 GTX118992 GTX127375
GTX100240 GTX116080 GTX48634 GTX82986 GTX50814 GTX60594 GTX50635 GTX39752 GTX61650 GTX39751 GTX61566 ZF124729 GTX60696 ZF124730 GTX60705 ZF125176 GTX61711
GTX110619 GTX129098 GTX88747 GTX60227 GTX59643
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N Engl J Med 2013;368:651-62.
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Physiology and pathology
Current trending of autophagy research
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Cancer
Development
Inflammation
Differentiation
Neurodegenerative diseases Immunity
Diabetes/obesity/pancreatitis
Infectious diseases Crohn’s disease
Cardiac/heart diseases
Liver diseases Physiology (basal autophagy)
Pathology (stimulated autophagy)
pu bl ica tio ns
2004~2014(E)
Current trending of autophagy research
Adapted from GoPubMed
Dual Roles of Cancer-associated Autophagy
Trends Mol Med. 2013 Jul;19(7):428-46.
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Dual Roles of Cancer-associated Autophagy
Trends Mol Med. 2013 Jul;19(7):428-46.
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Autophagy in oncology
Tumor suppressor
• Isolate damaged proteins & organelles to limit instable cell growth
• Promote cell death of cancerous cells
Loss of Beclin1 renders mice tumor- prone
Defects in autophagy result in sustained p62 (SQSTM1) expression and ROS production, which is sufficient to promote tumorigenesis
Cell. 2009 Jun 12;137(6):1062-75.
Autophagy in oncology
Tumor survival
• Favor tumor cells to survive metabolic stress
The increase in metabolic stress is offset by autophagy functions
Inactivate Atg5 accelerates the onset of KrasG12D-driven lung cancer, but
markedly impairs the tumor progression.
Nat Commun. 2014;5:3056;
Cold Spring Harb Symp Quant Biol. 2011;76:389-96.
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Autophagy and Cancer
Dual Roles of Autophagy for Chemotherapy
Cell Death Dis. 2013 Oct 10;4:e838.
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Autophagy and Cancer
Cell research, 2014, 24:69-79
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N Engl J Med 2013;368:651-62.
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Current trending of autophagy research
Keystone Symposia on Molecular and Cellular Biology
Autophagy : Fundamentals to Disease (E2)
May 23-28, 2014 Hyatt Regency Austin, Austin, Texas, USA
Scientific Organizers: Christina H. Eng, Daniel J. Klionsky, Guido Kroemer and Li Yu
(Sponsored by Cell Research and Shire Human Genetic Therapies)
Impact of Autophagy in Cancer
Guido Kroemer : Autophagy vs. anticancer immune response Ravi K. Amaravadi : Targeting autophagy vs. cancer therapy Jayanta Debnath : Autophagy vs. secretion and cancer Eileen P. White : Autophagy vs. cancer metabolism Pharmacological Manipulation of Autophagy
Christina H. Eng :(Pfizer) Autophagy components vs. oncology drug targets Natalie D’Amore : Targeting autophagy for cancer therapy
Junying Yuan : Chaperone-mediated autophagy vs. mutant p5 Autophagy and disease
Beth Levine : Autophagy and immunity
Andrea Ballabio : Transcriptional control of autophagy in health and disease Ken H. Cadwell : Anti-inflammatory functions of autophagy in Crohn’s Disease Junichi Sadoshima : Autophagy vs. Cardiomyopathy
Interplay between Autophagy, Metabolism and aging
Ana Maria Cuervo : Selective autophagy vs. metabolism in aging Frank Madeo : Spermidine vs. age associated disease Myung-shik Lee : Autophagy vs. obesity and diabetes
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Autophagy
Nature 2010, 466(7302): 68-76)
Functional integration of the Autophagy Interaction Network
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Autophagy
Daniel J. Klionsky and Vojo Deretic April 2010 (http://www.nature.com/nrm/posters/autophagy)
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Autophagy
Daniel J. Klionsky and Vojo Deretic April 2010 (http://www.nature.com/nrm/posters/autophagy)
Thank You
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