Imatinib and bortezomib induce the expression and distribution of anaphase-promoting complex adaptor protein Cdh1 in blast crisis of chronic myeloid leukemia.

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.
Authors	Qiang Wang, Hong Sheng Zhou, Kai Kai Huang, Xue Jie Jiang, Fu Qun Wu, Rui Cao, Chang Xin Yin, Li Bin Liao, Zhong Xin Zheng, Han He, Rong Lin, Zheng Shan Yi, Dan Xu, Mo Yang, Fan Yi Meng
Journal	International journal of oncology (Int J Oncol) Vol. 40 Issue 2 Pg. 418-26 (Feb 2012) ISSN: 1791-2423 [Electronic] Greece
PMID	22002244 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References	Antigens, CD Antineoplastic Agents Benzamides Boronic Acids CDH1 protein, human Cadherins Piperazines Pyrazines Pyrimidines S-Phase Kinase-Associated Proteins Cyclin-Dependent Kinase Inhibitor p27 Bortezomib Imatinib Mesylate
Topics	Adult Antigens, CD Antineoplastic Agents (pharmacology, therapeutic use) Benzamides Blast Crisis Boronic Acids (pharmacology) Bortezomib Cadherins (genetics, metabolism) Cell Cycle Checkpoints Cell Line, Tumor Cell Nucleus (metabolism) Cyclin-Dependent Kinase Inhibitor p27 (metabolism) Drug Resistance, Neoplasm Female Gene Expression (drug effects) Gene Knockdown Techniques Humans Imatinib Mesylate Leukemia, Myelogenous, Chronic, BCR-ABL Positive (drug therapy, pathology) Male Piperazines (pharmacology, therapeutic use) Pyrazines (pharmacology) Pyrimidines (pharmacology, therapeutic use) RNA Interference S-Phase Kinase-Associated Proteins (metabolism) Young Adult

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