Abstract
Chronic myeloid leukemia (CML) is a myeloproliferative disease which uniquely expresses a constitutively active tyrosine kinase, BCR/ABL. As a specific inhibitor of the BCR-ABL tyrosine kinase, imatinib becomes the first choice for the treatment of CML due to its high efficacy and low toxicity. However, the development of imatinib resistance limits the long-term treatment benefits of it in CML patients. In the present study, we aimed to investigate the roles of miR-202 in the regulation of imatinib sensitivity in CML cell lines and the possible mechanisms involved in this process. We found miR-202 was down-regulated in seven CML cell lines by quantitative reverse-transcription PCR (qRT-PCR) analysis. Overexpression of miR-202 significantly suppressed proliferation rates of CML cells. By establishing imatinib resistant cell lines originating from K562 and KU812 cells, we observed expressions of miR-202 were down-regulated by imatinib treatments and imatinib resistant CML cell lines exhibited lower level of miR-202. On the contrary, imatinib resistant CML cell lines displayed up-regulated glycolysis rate than sensitive cells with the evidence that glucose uptake, lactate production, and key glycolysis enzymes were elevated in imatinib resistant cells. Importantly, the imatinib resistant CML cell lines were more sensitive to glucose starvation and glycolysis inhibitors. In addition, we identified Hexokinase 2 (HK2) as a direct target of miR-202 in CML cell lines. Overexpression of miR-202 sensitized imatinib resistant CML through the miR-202-mediated glycolysis inhibition by targetting HK2. Finally, we provided the clinical relevance that miR-202 was down-regulated in CML patients and patients with lower miR-202 expression displayed higher HK2 expression. The present study will provide new aspects on the miRNA-modulated tyrosine kinase inhibitor (TKI) sensitivity in CML, contributing to the development of new therapeutic anticancer drugs.
Highlights
Chronic myeloid leukemia (CML), originating from a constitutively active tyrosine kinase, BCR/ABL1 which occurs spontaneously, is a myeloproliferative disease affecting older adults typically [1,2]
MiR-202 expressions were evaluated by quantitative reverse-transcription PCR and our results demonstrated that miR-202 was significantly down-regulated in seven CML cell lines compared with leukocytes from normal blood sample (Figure 1A), suggesting that miR-202 might act as a tumor suppressor in CML
Another publication reported that miR-203 was shown to be epigenetically suppressed in CML [29], suggesting a tumor inhibitory function of miR-203 in CML
Summary
Chronic myeloid leukemia (CML), originating from a constitutively active tyrosine kinase, BCR/ABL1 which occurs spontaneously, is a myeloproliferative disease affecting older adults typically [1,2]. It is well studied that the BCR/ABL fusion protein is essential and sufficient for the malignant transformation of CML [4,5]. Imatinib is tyrosine kinase inhibitor (TKI), which is first used as a CML treatment strategy through targetting the tyrosine kinase activity of Bcr-Abl [7]. It is a TKI of the 2-phenylamino pyrimidine class through blocking the inactive conformation of BCR-ABL protein [7].
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