Journal
APPLIED MICROBIOLOGY AND BIOTECHNOLOGY
Volume 103, Issue 23-24, Pages 9569-9582Publisher
SPRINGER
DOI: 10.1007/s00253-019-10127-3
Keywords
Imatinib resistance; Chronic myeloid leukemia; miR328; Lysosomal degradation; Exosome delivery
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Funding
- National Natural Science Foundation of China [NSFC 31572344, NSFC 31771507, NSFC 81400110]
- Shaanxi Provincial Science and Technology Department [2018ZDXM-SF-063]
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Imatinib resistance remains the biggest hurdle for the treatment of chronic myeloid leukemia (CML), with the underlying mechanisms not fully understood. In this study, we found that miR328 significantly and strikingly decreased among other miRNA candidates during the induction of imatinib resistance. Overexpression of miR328 sensitized resistant cells to imatinib via post-transcriptionally decreasing ABCG2 expression, while miR328 knockdown conferred imatinib resistance in parental K562 cells. Moreover, miR328 was found selectively degraded in the lysosomes of K562R cells, as inhibition of lysosome with chloroquine restored miR328 expression and increased sensitivity to imatinib. Moreover, delivery of alkalized exosomes increased endogenous miR328 expression. Compared with the corresponding controls, the alkalized exosomes with or without miR328 sensitized the chronic leukemia cells to imatinib. Taken together, our study has revealed that lysosomal clearance of miR328 in imatinib-resistant cells at least partially contributes to the drug resistance, while delivery of alkalized exosomes would sensitize the chromic leukemia cells to imatinib.
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