Macroautophagy modulates cellular response to proteasome inhibitors in cancer therapy.
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.
Wu
William K K
WK
Institute of Digestive Diseases, LKS Institute of Health and Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong, China. wukakei@cuhk.edu.hk
Sakamoto
Kathleen M
KM
Milani
Manuela
M
Aldana-Masankgay
Grace
G
Fan
Daiming
D
Wu
Kaichun
K
Lee
Chung W
CW
Cho
Chi H
CH
Yu
Jun
J
Sung
Joseph J Y
JJ
D051701:Activating Transcription Factor 4 / Q000378:metabolism; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001343:Autophagy; D001897:Boronic Acids / Q000627:therapeutic use; D000069286:Bortezomib; D004722:Endoribonucleases / Q000378:metabolism; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D000076222:Mechanistic Target of Rapamycin Complex 1; D008565:Membrane Proteins / Q000378:metabolism; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D046912:Multiprotein Complexes; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D061988:Proteasome Inhibitors; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011506:Proteins; D011719:Pyrazines / Q000627:therapeutic use; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases; D014157:Transcription Factors / Q000378:metabolism; D057149:Ubiquitinated Proteins / Q000378:metabolism; D014452:Ubiquitins / Q000037:antagonists & inhibitors*
C497109:ATF4 protein, human; D000970:Antineoplastic Agents; D001897:Boronic Acids; C477012:MAP1LC3A protein, human; D008565:Membrane Proteins; D008869:Microtubule-Associated Proteins; D046912:Multiprotein Complexes; D061988:Proteasome Inhibitors; D011506:Proteins; D011719:Pyrazines; D014157:Transcription Factors; D057149:Ubiquitinated Proteins; D014452:Ubiquitins; D051701:Activating Transcription Factor 4; D000069286:Bortezomib; C403982:ERN2 protein, human; D000076222:Mechanistic Target of Rapamycin Complex 1; D017346:Protein Serine-Threonine Kinases; D058570:TOR Serine-Threonine Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D004722:Endoribonucleases; C433811:HDAC6 protein, human; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases