Phenformin, but not metformin, delays development of T-cell acute lymphoblastic leukemia/lymphoma via cell-autonomous AMPK activation

Diana Vara Ciruelos, Madhumita Dandapani, Fiona M. Russell, Katarzyna Grzes, Abdelmadjid Atrih, Marc Foretz, Benoit Viollet, Douglas J. Lamont, Doreen A. Cantrell, D. Grahame Hardie (Lead / Corresponding author)

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Abstract

AMPK acts downstream of the tumor suppressor LKB1, yet its role in cancer has been controversial. AMPK is activated by biguanides such as metformin and phenformin, and metformin use in diabetics has been associated with reduced cancer risk. However, whether this is mediated by cell-autonomous AMPK activation within tumor progenitor cells has been unclear. We report that T-cell-specific loss of AMPK-1 caused accelerated growth of T-cell acute lymphoblastic leukemia/lymphoma (T-ALL) induced by PTEN loss in thymic T-cell progenitors. Oral administration of phenformin, but not metformin, delayed onset and growth of lymphomas, but only when T-cells expressed AMPK-1. This differential effect of biguanides correlated with detection of phenformin, but not metformin, in thymus. Phenformin also enhanced apoptosis in T-ALL cells, both in in vivo and in vitro. Thus, AMPK-1 can be a cell-autonomous tumor suppressor in the context of T-ALL, and phenformin may have potential for the prevention of some cancers.
Original languageEnglish
Pages (from-to)690-698.e4
Number of pages15
JournalCell Reports
Volume27
Issue number3
Early online date16 Apr 2019
DOIs
Publication statusPublished - 16 Apr 2019

Keywords

  • AMP-activated protein kinase
  • AMPK
  • T cell acute lymphoblastic leukemia/lymphoma
  • T-ALL
  • biguanides
  • metformin
  • phenformin

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