NEK2 induces autophagy-mediated bortezomib resistance by stabilizing Beclin-1 in multiple myeloma
Xia, He, Meng, Chen, Zhang, Wu, Zhu, Shen, Feng, Guan, Kuang, Guo, Lei, Wu, An, Li, Qiu, Zhan, Zhou (2020) NEK2 induces autophagy-mediated bortezomib resistance by stabilizing Beclin-1 in multiple myeloma Mol Oncol (IF: 6.6) 14(4) 763-778Abstract
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.© 2020 The Authors. Published by FEBS Press and John Wiley & Sons Ltd.
Links
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7138399http://www.ncbi.nlm.nih.gov/pubmed/31955515
http://dx.doi.org/10.1002/1878-0261.12641