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  • Title: Imatinib and bortezomib induce the expression and distribution of anaphase-promoting complex adaptor protein Cdh1 in blast crisis of chronic myeloid leukemia.
    Author: Wang Q, Zhou HS, Huang KK, Jiang XJ, Wu FQ, Cao R, Yin CX, Liao LB, Zheng ZX, He H, Lin R, Yi ZS, Xu D, Yang M, Meng FY.
    Journal: Int J Oncol; 2012 Feb; 40(2):418-26. PubMed ID: 22002244.
    Abstract:
    Anaphase promoting complex cofactor Cdh1 plays a critical role in tumor suppression and genomic stability in cancer. However, its role in chronic myeloid leukemia (CML) remains unclear. We treated both wild-type and imatinib-resistant K562 cells with imatinib or nilotinib and bortezomib, respectively. The siRNAs of Cdh1 and Skp2 were designed and transiently transfected with HiPerFect transfection reagent into CML cells. Expression of Cdh1-Skp2-p27 pathway proteins were detected by Western blotting. Cell cycle, cell apoptosis and cellular morphology were detected by flow cytometry and Wright staining. Our study revealed that Cdh1 was expressed at lower levels in imatinib-resistant CML blast crisis (BC) patients than imatinib-sensitive ones. Moreover, imatinib and bortezomib induced cell cycle quiescence or arrest, upregulation and nuclear relocation of Cdh1 in CML cells. Furthermore, nilotinib and bortezomib resulted in upregulation of Cdh1 in imatinib-resistant CML cells. Conversely, Cdh1 silencing resulted in stabilization of Skp2 and Cdc20, subsequently promoting G1-S transition and formation of multinucleated cells. Our study shows that TKIs and bortezomib can regulate the cell cycle and cell apoptosis via regulation of the expression and redistribution of Cdh1 in CML-BC, which sheds light on the orchestration of crosstalk between TKIs and bortezomib in imatinib-resistant CML-BC. Additionally, Cdh1 tends to play an important role in maintenance of genomic stability, the detailed mechanisms deserve further study.
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