Abstract
Macroautophagy and the ubiquitin-proteasome system are two complementary pathways for protein degradation. The former degrades long-lived proteins and damaged organelles while the later degrades short-lived proteins. Recent findings indicate that suppression of the ubiquitin-proteasome system by proteasome inhibitors induces macroautophagy through multiple pathways, including (1) accumulation of ubiquitinated proteins and activation of HDAC6; (2) activation of the IRE1-JNK pathway; (3) proteasomal stabilization of ATF4; (4) inhibition of mTOR complex 1 signaling; (5) reduced proteasomal degradation of LC3. Induction of macroautophagy attenuates the antitumor effect of proteasome inhibitors in various types of cancer. These findings suggest that inhibition of macroautophagy may represent a novel strategy to enhance cellular sensitivity to proteasome inhibition.
Copyright 2010 Elsevier Ltd. All rights reserved.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Review
MeSH terms
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Activating Transcription Factor 4 / metabolism
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Antineoplastic Agents / therapeutic use*
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Autophagy*
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Boronic Acids / therapeutic use
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Bortezomib
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Endoribonucleases / metabolism
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Histone Deacetylase 6
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Histone Deacetylases / metabolism
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Humans
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JNK Mitogen-Activated Protein Kinases / metabolism
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Mechanistic Target of Rapamycin Complex 1
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Membrane Proteins / metabolism
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Microtubule-Associated Proteins / metabolism
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Multiprotein Complexes
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Neoplasms / drug therapy*
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Neoplasms / metabolism
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Neoplasms / physiopathology
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Proteasome Inhibitors*
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Protein Serine-Threonine Kinases / metabolism
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Proteins
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Pyrazines / therapeutic use
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Signal Transduction / drug effects
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TOR Serine-Threonine Kinases
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Transcription Factors / metabolism
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Ubiquitinated Proteins / metabolism
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Ubiquitins / antagonists & inhibitors*
Substances
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ATF4 protein, human
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Antineoplastic Agents
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Boronic Acids
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MAP1LC3A protein, human
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Membrane Proteins
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Microtubule-Associated Proteins
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Multiprotein Complexes
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Proteasome Inhibitors
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Proteins
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Pyrazines
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Transcription Factors
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Ubiquitinated Proteins
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Ubiquitins
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Activating Transcription Factor 4
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Bortezomib
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ERN2 protein, human
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Mechanistic Target of Rapamycin Complex 1
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Protein Serine-Threonine Kinases
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TOR Serine-Threonine Kinases
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JNK Mitogen-Activated Protein Kinases
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Endoribonucleases
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HDAC6 protein, human
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Histone Deacetylase 6
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Histone Deacetylases