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.
Highlights
Chronic myeloid leukemia (CML) is characterized by the uncontrolled proliferation of myeloid cells [1]
We provided evidence that dasatinib promotes cellular apoptosis through inhibition of Akt/mammalian target of rapamycin (mTOR) activities, and prevents exosomal release through downregulation of beclin-1 and Vps34 -dependent autophagic activity, indicating distinct dasatinib-induced mechanisms of apoptotic response and exosomes release in imatinib-resistant CML cells
It has been shown that CML cell lines such as K562 and LAMA84 could release exosomes that may play an important role in modulating the tumor microenviroment and promoting
Summary
Chronic myeloid leukemia (CML) is characterized by the uncontrolled proliferation of myeloid cells [1]. The resistance to imatinib led to the development of dasatinib, the second generation of tyrosine kinase inhibitors, showing enhanced inhibitory potency toward BCR-ABL1 [2]. It was shown that imatinib treatment can increase autophagic activity by inhibition of the PI3K/Akt/mTOR pathway [9]. In the BCR-ABL+ LAMA cells and in the cultured primary leukemia cells, imatinib treatment led to activation of the PI3K/Akt/mTOR pathway [15]. The effects of the PI3K/Akt/mTOR signaling and autophagy activity on cellular apoptosis and exosomes release, as well as the potential efficacy of dasatinib were investigated in imatinib-resistant K562 cells (K562RIMT). We provided evidence that dasatinib promotes cellular apoptosis through inhibition of Akt/mTOR activities, and prevents exosomal release through downregulation of beclin-1 and Vps34 -dependent autophagic activity, indicating distinct dasatinib-induced mechanisms of apoptotic response and exosomes release in imatinib-resistant CML cells
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