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Drug Resist Updat. 2010 Jun;13(3):87-92. doi: 10.1016/j.drup.2010.04.003. Epub 2010 May 11.

Macroautophagy modulates cellular response to proteasome inhibitors in cancer therapy.

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Institute of Digestive Diseases, LKS Institute of Health and Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong, China.


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.

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