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Int. J. Mol. Sci. 2016, 17(4), 531; doi:10.3390/ijms17040531

Distinct Dasatinib-Induced Mechanisms of Apoptotic Response and Exosome Release in Imatinib-Resistant Human Chronic Myeloid Leukemia Cells

1
Department of Hematology, Harbin Medical University Second Hospital, Harbin 150086, China
2
Department of Pediatrics, Harbin Medical University Second Hospital, Harbin 150086, China
3
Department of Hematology and Lymphology, Harbin Medical University Cancer Hospital, Harbin 150086, China
*
Author to whom correspondence should be addressed.
Academic Editor: Charles J. Malemud
Received: 13 January 2016 / Revised: 25 March 2016 / Accepted: 1 April 2016 / Published: 8 April 2016
(This article belongs to the Section Biochemistry, Molecular and Cellular Biology)
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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 (K562RIMT). 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 K562RIMT 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 K562RIMT 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 K562RIMT cells. Inhibition of autophagy by spautin-1 or beclin-1 knockdown decreased exosomal release, but did not affect apoptosis in K562RIMT cells. In summary, in K562RIMT 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. View Full-Text
Keywords: Imatinib-resistant K562; mTOR; autophagy; apoptosis; exosome; dasatinib Imatinib-resistant K562; mTOR; autophagy; apoptosis; exosome; dasatinib
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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MDPI and ACS Style

Liu, J.; Zhang, Y.; Liu, A.; Wang, J.; Li, L.; Chen, X.; Gao, X.; Xue, Y.; Zhang, X.; Liu, Y. Distinct Dasatinib-Induced Mechanisms of Apoptotic Response and Exosome Release in Imatinib-Resistant Human Chronic Myeloid Leukemia Cells. Int. J. Mol. Sci. 2016, 17, 531.

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