Abstract
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.
Highlights
Multiple myeloma (MM) is the second most frequent hematological malignancy characterized by transformed clonal plasma cells in the bone marrow (BM) microenvironment, monoclonal immunoglobulin in the blood or urine, and associated organ dysfunctions (Palumbo and Anderson, 2011)
Our previous studies demonstrated high Never in mitosis-related kinase 2 (NEK2) is associated with poor prognosis in MM, and overexpression of NEK2 promotes BTZ resistance (Zhou et al, 2013)
We speculated that autophagy might be involved in NEK2-mediated BTZ resistance
Summary
Multiple myeloma (MM) is the second most frequent hematological malignancy characterized by transformed clonal plasma cells in the bone marrow (BM) microenvironment, monoclonal immunoglobulin in the blood or urine, and associated organ dysfunctions (Palumbo and Anderson, 2011). The combination of autologous stem cell transplantation (ASCT) and multiple chemotherapeutic drugs such as proteasome inhibitor [bortezomib (BTZ), carfilzomib, ixazomib], immunomodulatory drugs (thalidomide, lenalidomide, pomalidomide), alkylating agent (melphalan), and corticosteroid (dexamethasone) have significantly extended patient overall. Abbreviations BTZ, bortezomib; CQ, chloroquine; MM, multiple myeloma; MS, mass spectrometry; TEM, transmission electron microscopy. NEK2 induces autophagy-mediated bortezomib resistance survival in MM (Palumbo and Anderson, 2011). A main reason for the treatment failure and disease relapse is the appearance of drug-resistant subclones during therapy. A better understanding of the mechanisms by which drug resistance is caused is urgently required
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