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miR-199a-5p Represses Protective Autophagy and Overcomes Chemoresistance by Directly Targeting DRAM1 in Acute Myeloid

Yang Li1, Guojun Zhang1, Bin Wu1

  • 1Department of Hematology, Shengjing Hospital of China Medical University, Shenyang 110004, China.

Journal of Oncology
|October 23, 2019
PubMed

Insights

MicroRNA-199a-5p (miR-199a-5p) is reduced in drug-resistant acute myeloid leukemia (AML). Lower miR-199a-5p levels promote chemotherapy resistance by increasing autophagy via DRAM1, suggesting a new therapeutic target for AML.

Area of Science:

  • Molecular Biology
  • Cancer Biology
  • Genetics

Background:

  • Chemotherapy resistance is a major challenge in treating acute myeloid leukemia (AML).
  • The mechanisms underlying drug resistance in AML are complex and not fully understood.
  • MicroRNAs (miRNAs) play crucial roles in regulating gene expression and cellular processes, including drug resistance.

Purpose of the Study:

  • To investigate the role of miR-199a-5p in chemotherapy resistance in AML.
  • To identify the molecular mechanisms by which miR-199a-5p influences drug resistance.
  • To explore the potential of targeting the miR-199a-5p pathway for overcoming chemoresistance in AML.

Main Methods:

  • Quantitative real-time PCR to measure miR-199a-5p levels in AML patients and cell lines.
  • Cell viability assays to assess chemoresistance.
  • Western blotting and autophagy assays to evaluate autophagic activity.
  • Luciferase reporter assays and RNA immunoprecipitation to confirm direct targeting of DRAM1 by miR-199a-5p.
  • siRNA-mediated knockdown of DRAM1 to assess its role in chemoresistance.

Main Results:

  • miR-199a-5p levels were significantly decreased in refractory/relapsed AML patients and Adriamycin-resistant AML cells (K562/ADM) compared to sensitive cells.
  • Autophagic activity was higher in K562/ADM cells and contributed to acquired drug resistance.
  • miR-199a-5p directly targeted and inhibited the expression of damage regulator autophagy modulator 1 (DRAM1).
  • Downregulation of DRAM1 suppressed autophagy and restored chemosensitivity in K562/ADM cells.

Conclusions:

  • The miR-199a-5p/DRAM1/autophagy signaling pathway is a novel regulator of chemoresistance in AML.
  • Reduced miR-199a-5p levels promote chemoresistance by upregulating DRAM1 and enhancing autophagy.
  • This pathway represents a potential therapeutic target for overcoming drug resistance in AML.

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