Apigenin inhibits proliferation and induces apoptosis in human multiple myeloma cells through targeting the trinity of CK2, Cdc37 and Hsp90

Molecular Cancer

Research

Hai-Yan Zhu¹  Ming Zhao²  Zhi-Yan Du²  Xiao-Dan Yu²  Yuan-Ji Xu²  Xu-Hui Zhang²  Jian Ma³ 

[1] Department of Hematology, General Hospital of PLA, 100853, Beijing, China;Department of Stress Medicine, Institute of Basic Medical Sciences, Cognitive and Mental Health Research Center, 100850, Beijing, China;International Medical Center, General Hospital of PLA, 100853, Beijing, China;

关键词: Apigenin;    CK2;    Cdc37;    Hsp90;    Multiple myeloma (MM);   

DOI  :  10.1186/1476-4598-10-104

 received in 2011-03-11, accepted in 2011-08-29,  发布年份 2011

来源: Springer

【 摘 要 】

BackgroundMultiple myeloma (MM) is a B-cell malignancy that is largely incurable and is characterized by the accumulation of malignant plasma cells in the bone marrow. Apigenin, a common flavonoid, has been reported to suppress proliferation in a wide variety of solid tumors and hematological cancers; however its mechanism is not well understood and its effect on MM cells has not been determined.ResultsIn this study, we investigated the effects of apigenin on MM cell lines and on primary MM cells. Cell viability assays demonstrated that apigenin exhibited cytotoxicity against both MM cell lines and primary MM cells but not against normal peripheral blood mononuclear cells. Together, kinase assays, immunoprecipitation and western blot analysis showed that apigenin inhibited CK2 kinase activity, decreased phosphorylation of Cdc37, disassociated the Hsp90/Cdc37/client complex and induced the degradation of multiple kinase clients, including RIP1, Src, Raf-1, Cdk4 and AKT. By depleting these kinases, apigenin suppressed both constitutive and inducible activation of STAT3, ERK, AKT and NF-κB. The treatment also downregulated the expression of the antiapoptotic proteins Mcl-1, Bcl-2, Bcl-xL, XIAP and Survivin, which ultimately induced apoptosis in MM cells. In addition, apigenin had a greater effects in depleting Hsp90 clients when used in combination with the Hsp90 inhibitor geldanamycin and the histone deacetylase inhibitor vorinostat.ConclusionsOur results suggest that the primary mechanisms by which apigenin kill MM cells is by targeting the trinity of CK2-Cdc37-Hsp90, and this observation reveals the therapeutic potential of apigenin in treating multiple myeloma.

【 授权许可】

Unknown   
© Zhao et al; licensee BioMed Central Ltd. 2011. This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.