MLN4924, an NAE inhibitor, suppresses AKT and mTOR signaling via upregulation of REDD1 in human myeloma cells.
The function and survival of normal and malignant plasma cells depends on the elaborately regulated ubiquitin proteasome system. Proteasome inhibitors such as bortezomib have proved to be highly effective in the treatment of multiple myeloma (MM), and their effects are related to normal protein homeostasis which is critical for plasma cell survival. Many ubiquitin ligases are regulated by conjugation with NEDD8. Therefore, neddylation may also impact survival and proliferation of malignant plasma cells. Here, we show that MLN4924, a potent NEDD8 activating enzyme (NAE) inhibitor, induced cytotoxicity in MM cell lines, and its antitumor effect is associated with suppression of the AKT and mammalian target of rapamycin (mTOR) signaling pathways through increased expression of REDD1. Combining MLN4924 with the proteasome inhibitor bortezomib induces synergistic apoptosis in MM cell lines which can overcome the prosurvival effects of growth factors such as interleukin-6 and insulin-like growth factor-1. Altogether, our findings demonstrate an important function for REDD1 in MLN4924-induced cytotoxicity in MM and also provide a promising therapeutic combination strategy for myeloma.
Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory University, Atlanta, GA.
Yanyan
Y
Gu
Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory University, Atlanta, GA.
Jonathan L
JL
Kaufman
Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory University, Atlanta, GA.
Leon
L
Bernal
Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory University, Atlanta, GA.
Claire
C
Torre
Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory University, Atlanta, GA.
Shannon M
SM
Matulis
Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory University, Atlanta, GA.
R Donald
RD
Harvey
Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory University, Atlanta, GA.
Jing
J
Chen
Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory University, Atlanta, GA.
Shi-Yong
SY
Sun
Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory University, Atlanta, GA.
Lawrence H
LH
Boise
Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory University, Atlanta, GA.
Sagar
S
Lonial
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001897:Boronic Acids / Q000494:pharmacology; D000069286:Bortezomib; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003517:Cyclopentanes / Q000494:pharmacology*; D006801:Humans; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D061988:Proteasome Inhibitors / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011719:Pyrazines / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics*; D044764:Ubiquitin-Activating Enzymes / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects*
D000970:Antineoplastic Agents; D001897:Boronic Acids; D003517:Cyclopentanes; C469991:DDIT4 protein, human; D061988:Proteasome Inhibitors; D011719:Pyrazines; D011743:Pyrimidines; D014157:Transcription Factors; D000069286:Bortezomib; C546842:MTOR protein, human; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D044764:Ubiquitin-Activating Enzymes; C491802:NAE protein, human; C539933:pevonedistat