EEN regulates the proliferation and survival of multiple myeloma cells by potentiating IGF-1 secretion.
The molecular mechanisms of multiple myeloma are not well defined. EEN is an endocytosis-regulating molecule. Here we report that EEN regulates the proliferation and survival of multiple myeloma cells, by regulating IGF-1 secretion. In the present study, we observed that EEN expression paralleled with cell proliferation, EEN accelerated cell proliferation, facilitated cell cycle transition from G1 to S phase by regulating cyclin-dependent kinases (CDKs) pathway, and delayed cell apoptosis via Bcl2/Bax-mitochondrial pathway. Mechanistically, we found that EEN was indispensable for insulin-like growth factor-1 (IGF-1) secretion and the activation of protein kinase B-mammalian target of rapamycin (Akt-mTOR) pathway. Exogenous IGF-1 overcame the phenotype of EEN depletion, while IGF-1 neutralization overcame that of EEN over-expression. Collectively, these data suggest that EEN may play a pivotal role in excessive cell proliferation and insufficient cell apoptosis of bone marrow plasma cells in multiple myeloma. Therefore, EEN may represent a potential diagnostic marker or therapeutic target for multiple myeloma.
Guangzhou Institute of Forensic Science, Guangzhou, China; Department of Forensic Pathology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, China.
Er-Wen
EW
Huang
Department of Forensic Pathology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, China.
Sheng-Jiang
SJ
Xue
Department of Pharmacy, The Third Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China.
Xiao-Yan
XY
Li
Department of Pharmacology and Toxicology, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, China.
Suo-Wen
SW
Xu
Department of Forensic Pathology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, China.
Jian-Ding
JD
Cheng
Department of Forensic Pathology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, China.
Jin-Xiang
JX
Zheng
Guangzhou Institute of Forensic Science, Guangzhou, China.
He
H
Shi
Guangzhou Institute of Forensic Science, Guangzhou, China.
Guo-Li
GL
Lv
Guangzhou Institute of Forensic Science, Guangzhou, China.
Zhi-Gang
ZG
Li
Guangzhou Institute of Forensic Science, Guangzhou, China.
Yue
Y
Li
Guangzhou Institute of Forensic Science, Guangzhou, China.
Chang-Hui
CH
Liu
Guangzhou Institute of Forensic Science, Guangzhou, China.
Xiao-Hui
XH
Chen
Guangzhou Institute of Forensic Science, Guangzhou, China.
Hong
H
Liu
Department of Anaesthesiology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China. Electronic address: mdlijie@sina.com.
Jie
J
Li
Guangzhou Institute of Forensic Science, Guangzhou, China. Electronic address: liuchaogaj@21cn.com.
Chao
C
Liu
D017209:Apoptosis; D014408:Biomarkers, Tumor / Q000235:genetics / Q000502:physiology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival; D059585:G1 Phase Cell Cycle Checkpoints; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D009101:Multiple Myeloma / Q000378:metabolism / Q000473:pathology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D017526:Receptor, IGF Type 1 / Q000378:metabolism* / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
D014408:Biomarkers, Tumor; D047908:Intracellular Signaling Peptides and Proteins; C105159:SH3GL1 protein, human; C546842:MTOR protein, human; D017526:Receptor, IGF Type 1; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases
Apoptosis; EEN; IGF-1; Multiple myeloma; Proliferation