Journal
MOLECULAR ONCOLOGY
Volume 14, Issue 4, Pages 763-778Publisher
WILEY
DOI: 10.1002/1878-0261.12641
Keywords
autophagy; Beclin-1; multiple myeloma; NEK2; ubiquitination
Categories
Funding
- National Natural Science Foundation of China [81800209, 81570205, 81630007, 81974010]
- China Postdoctoral Science Foundation [2018M640762]
- Postdoctoral Science Foundation of Central South University [198465]
- Hunan Province Natural Science Foundation of China [2019JJ50838]
- Ministry of Science and Technology of China [2018YFA0107800]
- Strategic Priority Research Program of Central South University [ZLXD2017004]
- Open Sharing Fund for the Large-scale Instruments and Equipments of Central South University [CSUZC201948, CSUZC201949]
Ask authors/readers for more resources
NEK2 is associated with drug resistance in multiple cancers. Our previous studies indicated that high NEK2 confers inferior survival in multiple myeloma (MM); thus, a better understanding of the mechanisms by which NEK2 induces drug resistance in MM is required. In this study, we discovered that NEK2 enhances MM cell autophagy, and a combination of autophagy inhibitor chloroquine (CQ) and chemotherapeutic bortezomib (BTZ) significantly prevents NEK2-induced drug resistance in MM cells. Interestingly, NEK2 was found to bind and stabilize Beclin-1 protein but did not affect its mRNA expression and phosphorylation. Moreover, autophagy enhanced by NEK2 was significantly prevented by knockdown of Beclin-1 in MM cells, suggesting that Beclin-1 mediates NEK2-induced autophagy. Further studies demonstrated that Beclin-1 ubiquitination is decreased through NEK2 interaction with USP7. Importantly, knockdown of Beclin-1 sensitized NEK2-overexpressing MM cells to BTZ in vitro and in vivo. In conclusion, we identify a novel mechanism whereby autophagy is activated by the complex of NEK2/USP7/Beclin-1 in MM cells. Targeting the autophagy signaling pathway may provide a promising therapeutic strategy to overcome NEK2-induced drug resistance in MM.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available