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

Ming Zhao,Yuan-Ji Xu,Xu-Hui Zhang,Zhi-Yan Du,Jian Ma,Hai-Yan Zhu,Xiao-Dan Yu

doi:10.1186/1476-4598-10-104

Abstract

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.

Highlights

Multiple 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
We found that apigenin inhibited the proliferation of MM cells, and induced apoptosis of MM cells through the suppression of Casein kinase 2 (CK2) kinase and the reduction of Cdc37 phosphorylation
Apigenin inhibits CK2 kinase activity and induces growth inhibition and cell cycle arrest in MM cells Initially, we investigated the effects of apigenin on CK2 kinase activity and expression level and compared these

Summary

Introduction

Multiple 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. Multiple myeloma (MM) is a B-cell malignancy characterized by the accumulation of malignant plasma cells in the bone marrow. It has been shown that MM cell lines and highly purified malignant plasma cells in patients with MM expressed higher protein and CK2 activity levels than normal plasma cells and B lymphocytes [6]. In this regard, using siRNA to inhibit CK2 activity induced apoptosis and enhanced the cytotoxic effect of melphalan on MM cells. It was proposed that CK2 might play a pivotal role in controlling survival and sensitivity to chemotherapeutics of MM cells [6]. Some recent studies have demonstrated that CK2 controls Hsp chaperone machinery by phosphorylating a kinase-targeting molecular co-chaperone, Cdc37 [7,8]

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