title: Distinct Dasatinib-Induced Mechanisms of Apoptotic Response and Exosome Release in Imatinib-Resistant Human Chronic Myeloid Leukemia Cells.
abstract: Although dasatinib is effective in most imatinib mesylate (IMT)-resistant chronic myeloid leukemia (CML) patients, the underlying mechanism of its effectiveness in eliminating imatinib-resistant cells is only partially understood. This study investigated the effects of dasatinib on signaling mechanisms driving-resistance in imatinib-resistant CML cell line K562 (K562R(IMT)). Compared with K562 control cells, exsomal release, the phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt)/ mammalian target of rapamycin (mTOR) signaling and autophagic activity were increased significantly in K562R(IMT) cells and mTOR-independent beclin-1/Vps34 signaling was shown to be involved in exosomal release in these cells. We found that Notch1 activation-mediated reduction of phosphatase and tensin homolog (PTEN) was responsible for the increased Akt/mTOR activities in K562R(IMT) cells and treatment with Notch1 γ-secretase inhibitor prevented activation of Akt/mTOR. In addition, suppression of mTOR activity by rapamycin decreased the level of activity of p70S6K, induced upregulation of p53 and caspase 3, and led to increase of apoptosis in K562R(IMT) cells. Inhibition of autophagy by spautin-1 or beclin-1 knockdown decreased exosomal release, but did not affect apoptosis in K562R(IMT) cells. In summary, in K562R(IMT) cells dasatinib promoted apoptosis through downregulation of Akt/mTOR activities, while preventing exosomal release and inhibiting autophagy by downregulating expression of beclin-1 and Vps34. Our findings reveal distinct dasatinib-induced mechanisms of apoptotic response and exosomal release in imatinib-resistant CML cells.
authors.affiliation: Department of Hematology, Harbin Medical University Second Hospital, Harbin 150086, China. liujuancheng79@163.com.
authors.forename: Juan
authors.initials: J
authors.lastname: Liu
authors.affiliation: Department of Pediatrics, Harbin Medical University Second Hospital, Harbin 150086, China. zhangyujing73@gmail.com.
authors.forename: Yujing
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Hematology and Lymphology, Harbin Medical University Cancer Hospital, Harbin 150086, China. liuaichun65@126.com.
authors.forename: Aichun
authors.initials: A
authors.lastname: Liu
authors.affiliation: Department of Hematology, Harbin Medical University Second Hospital, Harbin 150086, China. jinghua_wang57@163.com.
authors.forename: Jinghua
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Hematology and Lymphology, Harbin Medical University Cancer Hospital, Harbin 150086, China. lilianqiao85@126.com.
authors.forename: Lianqiao
authors.initials: L
authors.lastname: Li
authors.affiliation: Department of Hematology, Harbin Medical University Second Hospital, Harbin 150086, China. chenxihan78@163.com.
authors.forename: Xi
authors.initials: X
authors.lastname: Chen
authors.affiliation: Department of Hematology, Harbin Medical University Second Hospital, Harbin 150086, China. gaoxinyujiang83@163.com.
authors.forename: Xinyu
authors.initials: X
authors.lastname: Gao
authors.affiliation: Department of Hematology, Harbin Medical University Second Hospital, Harbin 150086, China. xueyanming82@163.com.
authors.forename: Yanming
authors.initials: Y
authors.lastname: Xue
authors.affiliation: Department of Hematology, Harbin Medical University Second Hospital, Harbin 150086, China. zhangxiaominli81@163.com.
authors.forename: Xiaomin
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Hematology, Harbin Medical University Second Hospital, Harbin 150086, China. liuyaoliu87@163.com.
authors.forename: Yao
authors.initials: Y
authors.lastname: Liu
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001343:Autophagy / Q000187:drug effects; D045744:Cell Line, Tumor; D000069439:Dasatinib / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D055354:Exosomes / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D000068877:Imatinib Mesylate / Q000494:pharmacology*; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D000069439:Dasatinib; D000068877:Imatinib Mesylate; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; C546842:MTOR protein, human
keywords: Imatinib-resistant K562; apoptosis; autophagy; dasatinib; exosome; mTOR