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Metformin inhibits JAK2V617F activity in MPN cells by activating AMPK and PP2A complexes containing the B56α subunit

Ichiro Kawashima1, Keita Kirito1

  • 1Department of Hematology and Oncology, University of Yamanashi, Yamanashi, Japan.

Experimental Hematology
|August 31, 2016
PubMed

Insights

Metformin inhibits malignant cell growth by targeting the JAK2V617F kinase through reactive oxygen species and protein tyrosine phosphatase PP2A activation. This suggests a new therapeutic strategy combining metformin with ruxolitinib for myeloproliferative neoplasms.

Area of Science:

  • Oncology
  • Pharmacology
  • Molecular Biology

Background:

  • Metformin is known to inhibit malignant cell growth, primarily through mTOR pathway suppression or autophagy regulation.
  • The oncogenic kinase JAK2V617F is a key driver in myeloproliferative neoplasms.
  • Alternative mechanisms of metformin's anti-cancer effects warrant investigation.

Purpose of the Study:

  • To investigate novel mechanisms by which metformin inhibits malignant hematologic cell growth.
  • To explore metformin's effect on the activity of the JAK2V617F kinase.
  • To evaluate the potential of metformin in combination therapy for JAK2V617F-driven cancers.

Main Methods:

  • Cellular assays to measure reactive oxygen species (ROS) levels and kinase activity.
  • Western blotting and phosphatase assays to assess protein modifications and enzyme activity.
  • Combination therapy studies using metformin and ruxolitinib in relevant cell lines (HEL, SET-2).

Main Results:

  • Metformin inhibits JAK2V617F activity via two distinct pathways: increasing ROS to inhibit SHP-2 (AMPK-dependent) and activating PP2A phosphatase.
  • The PP2A complex containing the B56α subunit is identified as crucial for JAK2V617F inhibition by metformin.
  • Metformin enhances the antileukemic effects of ruxolitinib in HEL and SET-2 cells.

Conclusions:

  • Metformin exhibits anti-leukemic activity through novel mechanisms involving JAK2V617F inhibition.
  • The combination of metformin and ruxolitinib shows promise as a therapeutic strategy for JAK2V617F-positive myeloproliferative neoplasms.
  • Targeting PP2A complexes with the B56α subunit may offer a new treatment avenue for these malignancies.

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