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

Vara-Ciruelos, Diana; Dandapani, Madhumita; Russell, Fiona M.; Grzes, Katarzyna M.; Atrih, Abdelmadjid; Foretz, Marc; Viollet, Benoit; Lamont, Douglas J.; Cantrell, Doreen A.; Hardie, D. Grahame

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-a1 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-a1. 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-a1 can be a cell-autonomous tumor suppressor in the context of T-ALL, and phenformin may have potential for the prevention of some cancers.

Citation

Vara-Ciruelos, D., Dandapani, M., Russell, F. M., Grzes, K. M., Atrih, A., Foretz, M., Viollet, B., Lamont, D. J., Cantrell, D. A., & Hardie, D. G. (2019). Phenformin, But Not Metformin, Delays Development of T Cell Acute Lymphoblastic Leukemia/Lymphoma via Cell-Autonomous AMPK Activation. Cell Reports, 27(3), 690-698.e4. https://doi.org/10.1016/j.celrep.2019.03.067

• Journal Article Type: Article
• Acceptance Date: Mar 18, 2019
• Online Publication Date: Apr 16, 2019
• Publication Date: Apr 16, 2019
• Deposit Date: Nov 15, 2019
• Publicly Available Date: Nov 18, 2019
• Journal: Cell Reports
• Print ISSN: 2211-1247
• Electronic ISSN: 2211-1247
• Publisher: Cell Press
• Peer Reviewed: Peer Reviewed
• Volume: 27
• Issue: 3
• Pages: 690-698.e4
• DOI: https://doi.org/10.1016/j.celrep.2019.03.067
• Keywords: General Biochemistry, Genetics and Molecular Biology
• Public URL: https://nottingham-repository.worktribe.com/output/2142838
• Publisher URL: https://www.sciencedirect.com/science/article/pii/S2211124719303973?via%3Dihub
• Contract Date: Nov 15, 2019