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Applied Microbiology and Biotechnology

, Volume 103, Issue 23–24, pp 9569–9582 | Cite as

Targeted blocking of miR328 lysosomal degradation with alkalized exosomes sensitizes the chronic leukemia cells to imatinib

  • Yan Dong
  • Yao Lin
  • Xiaotong Gao
  • Yingxin Zhao
  • Zhuo Wan
  • Haotian Wang
  • Mengying Wei
  • Xutao Chen
  • Weiwei Qin
  • Guodong YangEmail author
  • Li LiuEmail author
Applied genetics and molecular biotechnology
  • 85 Downloads

Abstract

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.

Keywords

Imatinib resistance Chronic myeloid leukemia miR328 Lysosomal degradation Exosome delivery 

Notes

Funding information

This study is funded by the National Natural Science Foundation of China (NSFC 31572344 to Li Liu, NSFC 31771507 to Guodong Yang, NSFC 81400110 to Weiwei Qin, Shaanxi Provincial Science and Technology Department 2018ZDXM-SF-063).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

This article does not contain any studies with human participants or animals performed by any of the authors.

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Yan Dong
    • 1
  • Yao Lin
    • 2
  • Xiaotong Gao
    • 1
  • Yingxin Zhao
    • 1
  • Zhuo Wan
    • 1
  • Haotian Wang
    • 1
  • Mengying Wei
    • 3
  • Xutao Chen
    • 4
  • Weiwei Qin
    • 1
  • Guodong Yang
    • 3
    Email author
  • Li Liu
    • 1
    Email author
  1. 1.Department of Hematology, Tangdu HospitalFourth Military Medical UniversityXi’anChina
  2. 2.Department of Stomatology, the Second Affiliated hospitalShantou University Medical CollegeShantouChina
  3. 3.Department of Biochemistry and Molecular BiologyFourth Military Medical UniversityXi’anChina
  4. 4.Department of Implantation, School of StomatologyFourth Military Medical UniversityXi’anChina

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