Macroautophagy modulates cellular response to proteasome inhibitors in cancer therapy

Wu, William K.K.; Sakamoto, Kathleen M.; Milani, Manuela; Aldana-Masankgay, Grace; Fan, Daiming; Wu, Kaichun; Lee, Chung W.; Cho, Chi H.; Yu, Jun; Sung, Joseph J.Y.

doi:10.1016/j.drup.2010.04.003

« PreviousDrug Resistance Updates
Volume 13, Issue 3 , Pages 87-92, June 2010

Macroautophagy modulates cellular response to proteasome inhibitors in cancer therapy

William K.K. Wu
- Institute of Digestive Diseases, LKS Institute of Health and Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong, China
- Corresponding author at: 7/F, LKS Medical Sciences Building, Prince of Wales Hospital, Shatin, NT, Hong Kong, China. Tel.: +852 3763 6103; fax: +852 2144 5330.
Kathleen M. Sakamoto
- Division of Hematology-Oncology, Gwynne Hazen Cherry Memorial Laboratories, Mattel Children's Hospital UCLA, Jonsson Comprehensive Cancer Center, David Geffen School of Medicine, Molecular Biology Institute, California Nanosystems Institute, University of California, Los Angeles, CA, USA
Manuela Milani
- Growth Factor Group, Cancer Research UK, Molecular Oncology Laboratories, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Headington, Oxford, United Kingdom
Grace Aldana-Masankgay
- Division of Hematology-Oncology, Gwynne Hazen Cherry Memorial Laboratories, Mattel Children's Hospital UCLA, Jonsson Comprehensive Cancer Center, David Geffen School of Medicine, Molecular Biology Institute, California Nanosystems Institute, University of California, Los Angeles, CA, USA
Daiming Fan
- State Key Laboratory of Cancer Biology and Institute of Digestive Diseases, Xijing Hospital, Fourth Military Medical University, Xi’an, China
Kaichun Wu
- State Key Laboratory of Cancer Biology and Institute of Digestive Diseases, Xijing Hospital, Fourth Military Medical University, Xi’an, China
Chung W. Lee
- Institute of Digestive Diseases, LKS Institute of Health and Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong, China
Chi H. Cho
- Institute of Digestive Diseases, LKS Institute of Health and Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong, China
Jun Yu
- Institute of Digestive Diseases, LKS Institute of Health and Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong, China
Joseph J.Y. Sung
- Institute of Digestive Diseases, LKS Institute of Health and Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong, China
- Corresponding author at: 9/F, Clinical Sciences Building, Prince of Wales Hospital, Shatin, NT, Hong Kong, China. Tel.: +852 2632 3132; fax: +852 2645 1699.

Received 31 March 2010; received in revised form 20 April 2010; accepted 20 April 2010. published online 12 May 2010.

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.

Keywords: HDAC6, IRE1-JNK, ATF4, mTOR, LC3, Aggresome, Bortezomib