title: AEG-1 overexpression is essential for maintenance of malignant state in human AML cells via up-regulation of Akt1 mediated by AURKA activation.
abstract: Acute myeloid leukemia (AML) remains highly fatal, highlighting the need for improved understanding of signal pathways that can lead to the development of new therapeutic regimens targeting common molecular pathways shared across different AML subtypes. Here we demonstrate that astrocyte elevated gene-1 (AEG-1) is one of such pathways, involving in cell cycle and apoptosis regulation and contributing to enhanced proliferation and chemoresistance in HL-60 and U937 AML cells. The pleiotropic effects of AEG-1 on AML were found to correlate with two novel target genes, Aurora kinase A (AURKA) and Akt1. Down-regulation of AEG-1 by short-hairpin RNA (shRNA) could not only decrease AURKA expression both on mRNA and protein levels but also decrease the levels of pAkt473 and pAkt308 (the active forms of phosphorylated Akt), similar effect as using AURKA inhibitor Tozasertib (VX680). Furthermore, the AEG-1 shRNA-induced malignant phenotype changes could be mitigated by forced overexpression of AURKA through increased Akt1 activation and phosphorylation in AML cells. On the other hand, although exogenous expression of AEG-1 could increase both AURKA and Akt expression levels the simultaneous use of AURKA inhibitor Tozasertib blocked AEG-1's role of up-regulation of Akt expression in ECV304 cells, suggesting that AURKA might be a key mediator of AEG-1 in regulating Akt activation, and a key effector of AEG-1 in maintaining the malignant state of AML. Moreover, knockdown AEG-1 expression also changed the expression levels of PTEN, survivin and stathmin, the genes that have been reported to be involved in the development of several other malignant tumors. Our results provide evidence for AEG-1's carcinogenesis role in AML and reveal a novel functional link between AEG-1 and AURKA on Akt1 activation. AEG-1 can be an important candidate as a drug design target within AURKA signal pathway for more specific killing of AML cells while sparing normal cells.
authors.affiliation: Department of Medical Laboratory and Research Center, Tangdu Hospital, Fourth Military Medical University, Xi'an, China.
authors.forename: Min
authors.initials: M
authors.lastname: Long
authors.forename: Miaowang
authors.initials: M
authors.lastname: Hao
authors.forename: Ke
authors.initials: K
authors.lastname: Dong
authors.forename: Jianjun
authors.initials: J
authors.lastname: Shen
authors.forename: Xi
authors.initials: X
authors.lastname: Wang
authors.forename: Fang
authors.initials: F
authors.lastname: Lin
authors.forename: Li
authors.initials: L
authors.lastname: Liu
authors.forename: Junxia
authors.initials: J
authors.lastname: Wei
authors.forename: Yingmin
authors.initials: Y
authors.lastname: Liang
authors.forename: Jian
authors.initials: J
authors.lastname: Yang
authors.forename: Fangna
authors.initials: F
authors.lastname: Gu
authors.forename: Huizhong
authors.initials: H
authors.lastname: Zhang
mesh_terms: D000970:Antineoplastic Agents / Q000633:toxicity; D064096:Aurora Kinase A; D064127:Aurora Kinases; D015815:Cell Adhesion Molecules / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D002470:Cell Survival / Q000187:drug effects; D018385:Centrosome / Q000378:metabolism; D002945:Cisplatin / Q000633:toxicity; D015536:Down-Regulation / Q000187:drug effects; D018922:HL-60 Cells; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000378:metabolism; D015470:Leukemia, Myeloid, Acute / Q000378:metabolism* / Q000473:pathology; D008565:Membrane Proteins; D051059:PTEN Phosphohydrolase / Q000378:metabolism; D010641:Phenotype; D010766:Phosphorylation; D010879:Piperazines / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D034622:RNA Interference; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D016601:RNA-Binding Proteins; D050777:Stathmin / Q000378:metabolism; D000077022:Survivin; D020298:U937 Cells; D015854:Up-Regulation / Q000187:drug effects; D003521:Cyclopropanes; D011720:Pyrazoles; D011743:Pyrimidines
chemical_list: D000970:Antineoplastic Agents; D064096:Aurora Kinase A; D064127:Aurora Kinases; D015815:Cell Adhesion Molecules; D002945:Cisplatin; D051034:Inhibitor of Apoptosis Proteins; D008565:Membrane Proteins; D051059:PTEN Phosphohydrolase; D010879:Piperazines; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D016601:RNA-Binding Proteins; D050777:Stathmin; D000077022:Survivin; C107489:BIRC5 protein, human; C483039:MTDH protein, human; C484810:tozasertib; D003521:Cyclopropanes; D011720:Pyrazoles; D011743:Pyrimidines; C576917:AURKA protein, human; C494929:PTEN protein, human