Phenformin, But Not Metformin, Delays Development of T Cell Acute Lymphoblastic Leukemia/Lymphoma via Cell-Autonomous AMPK Activation.

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-α1 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-α1. 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 vivo and in vitro. Thus, AMPK-α1 can be a cell-autonomous tumor suppressor in the context of T-ALL, and phenformin may have potential for the prevention of some cancers.

• Authors: Diana Vara-Ciruelos, Madhumita Dandapani, Fiona M Russell, Katarzyna M Grzes, Abdelmadjid Atrih, Marc Foretz, Benoit Viollet, Douglas J Lamont, Doreen A Cantrell, D Grahame Hardie
• Journal: Cell reports (Cell Rep) Vol. 27 Issue 3 Pg. 690-698.e4 (04 16 2019) ISSN: 2211-1247 [Electronic] United States
• PMID: 30995468 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.

Chemical References

• Hypoglycemic Agents
• Metformin
• Phenformin
• Mechanistic Target of Rapamycin Complex 1
• AMP-Activated Protein Kinases
• PTEN Phosphohydrolase
• Pten protein, mouse
• Sirolimus

Topics

• AMP-Activated Protein Kinases (deficiency, genetics, metabolism)
• Administration, Oral
• Animals
• Cell Proliferation (drug effects)
• Disease Models, Animal
• Disease-Free Survival
• Female
• Glycolysis (drug effects)
• Hypoglycemic Agents (pharmacology, therapeutic use)
• Male
• Mechanistic Target of Rapamycin Complex 1 (antagonists & inhibitors, metabolism)
• Metformin (pharmacology)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• PTEN Phosphohydrolase (deficiency, genetics)
• Phenformin (pharmacology, therapeutic use)
• Precursor T-Cell Lymphoblastic Leukemia-Lymphoma (drug therapy, mortality, pathology)
• Signal Transduction (drug effects)
• Sirolimus (pharmacology)