Overexpression of miR-202 re-sensitizes imatinib resistant chronic myeloid leukemia cells through targeting Hexokinase 2 (HK2)

CML is a myeloproliferative disease which expresses an active tyrosine kinase, BCR/ABL. As a specific inhibitor of BCR-ABL tyrosine kinase, imatinib becomes the first choice for treatment of CML due to its high efficacy and low toxicity. However, the development of imatinib resistance limits the long-term treatment benefit. so, we aimed to investigate the roles of miR-202 in the regulation of imatinib sensitivity in CML cell lines and the possible mechanisms involved. We found miR-202 was downregulated in seven CML cell lines by qRT-PCR analysis. Overexpression of miR-202 significantly suppressed proliferation rates of CML cell. By establishing imatinib resistant cell lines originating from K562 and KU812 cells, we observed expressions of miR-202 were downregulated by imatinib treatments and imatinib resistant CML cell lines exhibited lower level of miR-202. On the contrary, imatinib resistant CML cell lines displayed upregulated 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 as a target of miR-202 in CML. Overexpression of miR-202 sensitized imatinib resistant CML through the miR-202-mediated glycolysis inhibition by targeting Hexokinase 2. Finally, we provided the clinical relevance miR-202 was downregulated in CML and patients with lower miR-202 expression displayed higher Hexokinase 2 expression. This study will provide new aspects on tyrosine kinase inhibitor sensitivity in CML, contributing to the development of new therapeutic anticancer drugs.