NEK2 induces autophagy‐mediated bortezomib resistance by stabilizing Beclin‐1 in multiple myeloma

Molecular Oncology

卷:14

Yanjuan He¹  Wen Zhou¹  Jiliang Xia¹  Fenghuang Zhan²  Yi Shen³  Shilian Chen⁴  Qian Lei⁴  Xuan Wu⁴  Chunmei Kuang⁴  Guancheng Li⁴  Yinghong Zhu⁴  Bin Meng⁴  Yongjun Guan⁴  Jiaojiao Guo⁴  Jingyu Zhang⁴  Gang An⁵  Lugui Qiu⁵  Yangbowen Wu⁶  Xiangling Feng⁶ 

[1] Department of Hematology Xiangya Hospital Central South University Changsha China;

[2] Department of Medicine Division of Hematology, Oncology and Blood and Marrow Transplantation Holden Comprehensive Cancer Center University of Iowa IA USA;

[3] Department of Orthopaedic Surgery Second Xiangya Hospital Central South University Changsha China;

[4] Key Laboratory for Carcinogenesis and Invasion Chinese Ministry of Education Key Laboratory of Carcinogenesis Chinese Ministry of Health Cancer Research Institute School of Basic Medical Sciences Central South University Changsha China;

[5] State Key Laboratory of Experimental Hematology Institute of Hematology & Blood Diseases Hospital Chinese Academy of Medical Science & Peking Union Medical College Tianjin China;

[6] Xiangya School of Public Health Central South University Changsha China;

关键词: autophagy;    Beclin‐1;    multiple myeloma;    NEK2;    ubiquitination;   

DOI  :  10.1002/1878-0261.12641

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown