Blockade of Y177 and Nuclear Translocation of Bcr-Abl Inhibits Proliferation and Promotes Apoptosis in Chronic Myeloid Leukemia Cells

Department of Clinical Hematology, Key Laboratory of Laboratory Medical Diagnostics Designated by the Ministry of Education, Chongqing Medical University, Chongqing 400016, China

Department of Hematology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China

Author to whom correspondence should be addressed.

Academic Editor: Hsueh-Wei Chang

Int. J. Mol. Sci. 2017, 18(3), 537; https://doi.org/10.3390/ijms18030537

Received: 2 January 2017 / Revised: 9 February 2017 / Accepted: 23 February 2017 / Published: 2 March 2017

(This article belongs to the Special Issue Tumor Targeting Therapy and Selective Killing)

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Abstract

The gradual emerging of resistance to imatinib urgently calls for the development of new therapy for chronic myeloid leukemia (CML). The fusion protein Bcr-Abl, which promotes the malignant transformation of CML cells, is mainly located in the cytoplasm, while the c-Abl protein which is expressed in the nucleus can induce apoptosis. Based on the hetero-dimerization of FKBP (the 12-kDa FK506- and rapamycin-binding protein) and FRB (the FKBP-rapamycin binding domain of the protein kinase, mTOR) mediated by AP21967, we constructed a nuclear transport system to induce cytoplasmic Bcr-Abl into nuclear. In this study, we reported the construction of the nuclear transport system, and we demonstrated that FN3R (three nuclear localization signals were fused to FRBT2098L with a FLAG tag), HF2S (two FKBP domains were in tandem and fused to the SH2 domain of Grb2 with an HA tag) and Bcr-Abl form a complexus upon AP21967. Bcr-Abl was imported into the nucleus successfully by the nuclear transport system. The nuclear transport system inhibited CML cell proliferation through mitogen-activated protein kinase (MAPK) and signal transducer and activator of transcription 5 (STAT5) pathways mainly by HF2S. It was proven that nuclear located Bcr-Abl induced CML cell (including imatinib-resistant K562G01 cells) apoptosis by activation of p73 and its downstream molecules. In summary, our study provides a new targeted therapy for the CML patients even with Tyrosine Kinase Inhibitor (TKI)-resistance. View Full-Text

Keywords: Bcr-Abl; nuclear; transport; proliferation; apoptosis

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MDPI and ACS Style

Li, Q.; Huang, Z.; Gao, M.; Cao, W.; Xiao, Q.; Luo, H.; Feng, W. Blockade of Y177 and Nuclear Translocation of Bcr-Abl Inhibits Proliferation and Promotes Apoptosis in Chronic Myeloid Leukemia Cells. Int. J. Mol. Sci. 2017, 18, 537. https://doi.org/10.3390/ijms18030537

AMA Style

Li Q, Huang Z, Gao M, Cao W, Xiao Q, Luo H, Feng W. Blockade of Y177 and Nuclear Translocation of Bcr-Abl Inhibits Proliferation and Promotes Apoptosis in Chronic Myeloid Leukemia Cells. International Journal of Molecular Sciences. 2017; 18(3):537. https://doi.org/10.3390/ijms18030537

Chicago/Turabian Style

Li, Qianyin, Zhenglan Huang, Miao Gao, Weixi Cao, Qin Xiao, Hongwei Luo, and Wenli Feng. 2017. "Blockade of Y177 and Nuclear Translocation of Bcr-Abl Inhibits Proliferation and Promotes Apoptosis in Chronic Myeloid Leukemia Cells" International Journal of Molecular Sciences 18, no. 3: 537. https://doi.org/10.3390/ijms18030537

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Blockade of Y177 and Nuclear Translocation of Bcr-Abl Inhibits Proliferation and Promotes Apoptosis in Chronic Myeloid Leukemia Cells

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