title: Knock-down of CIAPIN1 sensitizes K562 chronic myeloid leukemia cells to Imatinib by regulation of cell cycle and apoptosis-associated members via NF-κB and ERK5 signaling pathway.
abstract: CIAPIN1 (cytokine-induced apoptosis inhibitor 1) was recently identified as an essential downstream effector of the Ras signaling pathway. However, its potential role in regulating myeloid leukemia cells sensitivity to Imatinib remains unclear. In this study, we found depletion of CIAPIN1 inhibited proliferation and triggered more apoptosis of K562CML (chronic myeloid leukemia) cells with or without Imatinib treatment. Meanwhile, CIAPIN1 depletion decreased ERK5 phosphorylation and NF-κB activity. Importantly, treating CIAPIN1-depleted K562 cells with ERK5 signaling pathway specific inhibitor, XMD8-92, further inhibited proliferation and promoted apoptosis with or without Imatinib treatment. Treatment with the NF-κB specific inhibitor, Bay 11-7082, induced nearly the same inhibition of proliferation and promotion of apoptosis conferred by CIAPIN1 depletion as was observed with XMD8-92 treatment. Further, XMD8-92 and Bay 11-7082 synergistically inhibited proliferation and promoted apoptosis of CIAPIN1-depleted K562 cells with or without Imatinib treatment. The nude mice transplantation model was also performed to confirm the enhanced sensitivity of CIAPIN1-depleted K562 cells to Imatinib. Thus, our results provided a potential management by which CIAPIN1 knock-down might have a crucial impact on enhancing sensitivity of K562 cells to Imatinib in the therapeutic approaches, indicating that CIAPIN1 knock-down might serve as a combination with chemotherapeutical agents in leukemia diseases therapy.
authors.affiliation: Department of Immunology, Tianjin Medical University Cancer Institute and Hospital, Key Laboratory of Cancer Immunology and Biotherapy, National Clinical Research Center of Cancer, Tianjin 300060, China; State Key Laboratory of Experimental Hematology, Institute of Hematology and Hospital of Blood Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Nanjing Road 288, Tianjin 300020, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Experimental Hematology, Institute of Hematology and Hospital of Blood Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Nanjing Road 288, Tianjin 300020, China.
authors.forename: Qinghua
authors.initials: Q
authors.lastname: Li
authors.affiliation: Department of Breast Cancer Pathology and Research Laboratory, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Key Laboratory of Breast Cancer Prevention and Therapy, Tianjin Medical University, Ministry of Education, Key Laboratory of Cancer Prevention and Therapy, State Key Laboratory of Breast Cancer Research, Tianjin 300060, China.
authors.forename: Chijuan
authors.initials: C
authors.lastname: Wang
authors.affiliation: Department of Hepatobiliary Surgery, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin 300060, China.
authors.forename: Qingqing
authors.initials: Q
authors.lastname: Xiong
authors.affiliation: State Key Laboratory of Experimental Hematology, Institute of Hematology and Hospital of Blood Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Nanjing Road 288, Tianjin 300020, China.
authors.forename: Yani
authors.initials: Y
authors.lastname: Lin
authors.affiliation: Department of Immunology, Tianjin Medical University Cancer Institute and Hospital, Key Laboratory of Cancer Immunology and Biotherapy, National Clinical Research Center of Cancer, Tianjin 300060, China.
authors.forename: Qian
authors.initials: Q
authors.lastname: Sun
authors.affiliation: Department of Immunology, Tianjin Medical University Cancer Institute and Hospital, Key Laboratory of Cancer Immunology and Biotherapy, National Clinical Research Center of Cancer, Tianjin 300060, China.
authors.forename: Hao
authors.initials: H
authors.lastname: Jin
authors.affiliation: Department of Immunology, Tianjin Medical University Cancer Institute and Hospital, Key Laboratory of Cancer Immunology and Biotherapy, National Clinical Research Center of Cancer, Tianjin 300060, China.
authors.forename: Fan
authors.initials: F
authors.lastname: Yang
authors.affiliation: Department of Immunology, Tianjin Medical University Cancer Institute and Hospital, Key Laboratory of Cancer Immunology and Biotherapy, National Clinical Research Center of Cancer, Tianjin 300060, China.
authors.forename: Xiubao
authors.initials: X
authors.lastname: Ren
authors.affiliation: State Key Laboratory of Experimental Hematology, Institute of Hematology and Hospital of Blood Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Nanjing Road 288, Tianjin 300020, China. Electronic address: pang@ihcams.ac.cn.
authors.forename: Tianxiang
authors.initials: T
authors.lastname: Pang
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D002453:Cell Cycle / Q000187:drug effects / Q000502:physiology*; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D005260:Female; D055785:Gene Knockdown Techniques / Q000379:methods; D006801:Humans; D000068877:Imatinib Mesylate / Q000494:pharmacology* / Q000627:therapeutic use; D047908:Intracellular Signaling Peptides and Proteins / Q000172:deficiency* / Q000235:genetics; D020014:K562 Cells; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D048054:Mitogen-Activated Protein Kinase 7 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology
chemical_list: D000970:Antineoplastic Agents; C489114:CIAPIN1 protein, human; D047908:Intracellular Signaling Peptides and Proteins; D016328:NF-kappa B; D000068877:Imatinib Mesylate; D048054:Mitogen-Activated Protein Kinase 7
keywords: CIAPIN1; ERK5; Imatinib; K562 cells; NF-κB