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

doi:10.1016/j.celrep.2019.03.067

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 language	English
Pages (from-to)	690-698.e4
Number of pages	15
Journal	Cell Reports
Volume	27
Issue number	3
Early online date	16 Apr 2019
DOIs	https://doi.org/10.1016/j.celrep.2019.03.067
Publication status	Published - 16 Apr 2019

Keywords

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

ASJC Scopus subject areas

General Biochemistry,Genetics and Molecular Biology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.celrep.2019.03.067Licence: CC BY

Final Published VersionFinal published version, 3.35 MBLicence: CC BY

Cite this

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title = "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-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.",

keywords = "AMP-activated protein kinase, AMPK, T cell acute lymphoblastic leukemia/lymphoma, T-ALL, biguanides, metformin, phenformin",

author = "{Vara Ciruelos}, Diana and Madhumita Dandapani and Russell, {Fiona M.} and Katarzyna Grzes and Abdelmadjid Atrih and Marc Foretz and Benoit Viollet and Lamont, {Douglas J.} and Cantrell, {Doreen A.} and Hardie, {D. Grahame}",

note = "DVC and DGH were supported by a Programme Grant (C37030/A15101) from Cancer Research UK and MD by a Clinical PhD studentship from the Wellcome Trust. DGH and DAC were also indirectly supported by the companies funding the Division of Signal Transduction Therapy at Dundee (Boehringer-Ingelheim, GlaxoSmithKline and Merck Serono). ",

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T1 - Phenformin, but not metformin, delays development of T-cell acute lymphoblastic leukemia/lymphoma via cell-autonomous AMPK activation

AU - Vara Ciruelos, Diana

AU - Dandapani, Madhumita

AU - Russell, Fiona M.

AU - Grzes, Katarzyna

AU - Atrih, Abdelmadjid

AU - Foretz, Marc

AU - Viollet, Benoit

AU - Lamont, Douglas J.

AU - Cantrell, Doreen A.

AU - Hardie, D. Grahame

N1 - DVC and DGH were supported by a Programme Grant (C37030/A15101) from Cancer Research UK and MD by a Clinical PhD studentship from the Wellcome Trust. DGH and DAC were also indirectly supported by the companies funding the Division of Signal Transduction Therapy at Dundee (Boehringer-Ingelheim, GlaxoSmithKline and Merck Serono).

PY - 2019/4/16

Y1 - 2019/4/16

N2 - 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.

AB - 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.

KW - AMP-activated protein kinase

KW - AMPK

KW - T cell acute lymphoblastic leukemia/lymphoma

KW - T-ALL

KW - biguanides

KW - metformin

KW - phenformin

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JO - Cell Reports

JF - Cell Reports

IS - 3

ER -

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

Abstract

Keywords

ASJC Scopus subject areas

UN SDGs

Access to Document

Other files and links

Fingerprint

Rab Detection Initiative (Joint with Stanford School of Medicine, Max Plank Institute, Neuroscience Research Australia and Parkinsons Institute California)

AMP-Activated Protein Kinase - A Tumour Suppressor that Opposes the Metabolic Changes in Proliferating Cells (Programme Grant)

Serine Kinase Pathways that Determine T Lymphocyte Activation and Cell Fate Choices (Principal Research Fellowship renewal)

Cantrell, Doreen

Cite this

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

Abstract

Keywords

ASJC Scopus subject areas

UN SDGs

Access to Document

Other files and links

Fingerprint

Projects

Rab Detection Initiative (Joint with Stanford School of Medicine, Max Plank Institute, Neuroscience Research Australia and Parkinsons Institute California)

AMP-Activated Protein Kinase - A Tumour Suppressor that Opposes the Metabolic Changes in Proliferating Cells (Programme Grant)

Serine Kinase Pathways that Determine T Lymphocyte Activation and Cell Fate Choices (Principal Research Fellowship renewal)

Profiles

Cantrell, Doreen

Cite this