AMPK Activation by Metformin Promotes Survival of Dormant ER
AMP-Activated Protein Kinases
/ metabolism
Animals
Aromatase Inhibitors
/ pharmacology
Breast Neoplasms
/ pathology
Cell Line, Tumor
Cell Proliferation
/ drug effects
Cell Survival
/ drug effects
Chemotherapy, Adjuvant
/ methods
Estrogens
/ biosynthesis
Female
Humans
Metformin
/ pharmacology
Mice
Neoadjuvant Therapy
/ methods
Receptors, Estrogen
/ metabolism
Signal Transduction
/ drug effects
Xenograft Model Antitumor Assays
Journal
Clinical cancer research : an official journal of the American Association for Cancer Research
ISSN: 1557-3265
Titre abrégé: Clin Cancer Res
Pays: United States
ID NLM: 9502500
Informations de publication
Date de publication:
15 07 2020
15 07 2020
Historique:
received:
21
01
2020
revised:
01
04
2020
accepted:
15
04
2020
pubmed:
24
4
2020
medline:
3
11
2021
entrez:
24
4
2020
Statut:
ppublish
Résumé
Despite adjuvant endocrine therapy for patients with estrogen receptor alpha (ER)-positive breast cancer, dormant residual disease can persist for years and eventually cause tumor recurrence. We sought to deduce mechanisms underlying the persistence of dormant cancer cells to identify therapeutic strategies. Mimicking the aromatase inhibitor-induced depletion of estrogen levels used to treat patients, we developed preclinical models of dormancy in ER Dormant breast cancer cells exhibited upregulated 5' adenosine monophosphate-activated protein kinase (AMPK) levels and activity, and upregulated fatty acid oxidation. While the antidiabetes AMPK-activating drug metformin slowed the estrogen-driven growth of cells and tumors, metformin promoted the persistence of estrogen-deprived cells and tumors through increased mitochondrial respiration driven by fatty acid oxidation. Pharmacologic or genetic inhibition of AMPK or fatty acid oxidation promoted clearance of dormant residual disease, while dietary fat increased tumor cell survival. AMPK has context-dependent effects in cancer, cautioning against the widespread use of an AMPK activator across disease settings. The development of therapeutics targeting fat metabolism is warranted in ER
Identifiants
pubmed: 32321715
pii: 1078-0432.CCR-20-0269
doi: 10.1158/1078-0432.CCR-20-0269
pmc: PMC7367755
mid: NIHMS1587096
doi:
Substances chimiques
Aromatase Inhibitors
0
Estrogens
0
Receptors, Estrogen
0
Metformin
9100L32L2N
AMP-Activated Protein Kinases
EC 2.7.11.31
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
3707-3719Subventions
Organisme : NCI NIH HHS
ID : R01 CA200994
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA023108
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA126618
Pays : United States
Organisme : NCI NIH HHS
ID : F31 CA220936
Pays : United States
Organisme : NCI NIH HHS
ID : F30 CA216966
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA211869
Pays : United States
Informations de copyright
©2020 American Association for Cancer Research.
Références
Cell. 2012 Aug 17;150(4):764-79
pubmed: 22901808
Lancet Oncol. 2013 Sep;14(10):933-42
pubmed: 23932548
Nat Rev Cancer. 2015 Apr;15(4):238-47
pubmed: 25801619
Nature. 2016 Feb 18;530(7590):288-9
pubmed: 26887490
Clin Cancer Res. 2004 Aug 15;10(16):5342-8
pubmed: 15328170
Pharmacogenomics J. 2012 Feb;12(1):10-21
pubmed: 20697427
J Cardiovasc Electrophysiol. 2006 May;17 Suppl 1:S169-S177
pubmed: 16686675
Cell Metab. 2016 Apr 12;23(4):567-8
pubmed: 27076069
Clin Sci (Lond). 2012 Mar;122(6):253-70
pubmed: 22117616
Nat Cell Biol. 2013 Jul;15(7):807-17
pubmed: 23728425
J Am Med Inform Assoc. 2015 Jan;22(1):179-91
pubmed: 25053577
Lancet Oncol. 2010 Dec;11(12):1135-41
pubmed: 21087898
Cell. 2016 Mar 24;165(1):45-60
pubmed: 27015306
Oncogene. 2002 Sep 5;21(39):6082-90
pubmed: 12203120
J Clin Oncol. 2009 Jul 1;27(19):3117-25
pubmed: 19451425
Clin Pharmacokinet. 2011 Feb;50(2):81-98
pubmed: 21241070
J Clin Oncol. 2013 Sep 1;31(25):3083-90
pubmed: 23897954
Clin Cancer Res. 2017 Feb 15;23(4):946-953
pubmed: 27601592
J Thorac Oncol. 2012 Dec;7(12):1755-1766
pubmed: 23154546
Oncogene. 2014 Nov 6;33(45):5251-61
pubmed: 24186207
Clin Breast Cancer. 2015 Oct;15(5):307-12
pubmed: 25922284
Cancer Res. 2013 May 15;73(10):2929-35
pubmed: 23644529
Nat Med. 2011 Oct 30;17(11):1498-503
pubmed: 22037646
Clin Cancer Res. 2004 Dec 15;10(24):8152-62
pubmed: 15623589
Cell Metab. 2016 Apr 12;23(4):649-62
pubmed: 27076078
Breast Cancer Res. 2015 Jun 26;17:88
pubmed: 26111812
Herz. 2002 Nov;27(7):621-36
pubmed: 12439634
J Clin Med. 2019 Dec 11;8(12):
pubmed: 31835708
Breast Cancer Res. 2019 Jan 7;21(1):2
pubmed: 30616553
Cancer Res. 2011 Jul 1;71(13):4366-72
pubmed: 21540236
Breast Cancer Res. 2008;10(5):R76
pubmed: 18793387
Breast Cancer Res. 2009;11(4):R59
pubmed: 19664291
Gen Comp Endocrinol. 2012 Jan 1;175(1):188-93
pubmed: 22137913
J Biol Chem. 1994 Sep 2;269(35):22162-8
pubmed: 7915280
Mol Imaging Radionucl Ther. 2012 Apr;21(1):23-8
pubmed: 23486256
Clin Cancer Res. 2014 Aug 1;20(15):3962-73
pubmed: 24916694
Proc Natl Acad Sci U S A. 2005 Oct 25;102(43):15545-50
pubmed: 16199517
Breast Cancer Res Treat. 2019 Apr;174(2):433-442
pubmed: 30536182
Nat Rev Cancer. 2013 Apr;13(4):227-32
pubmed: 23446547
Cancer Res. 2014 Dec 1;74(23):6750-7
pubmed: 25411345
PLoS One. 2014 Apr 25;9(4):e96183
pubmed: 24769813
Cancer Res. 2007 Nov 15;67(22):10804-12
pubmed: 18006825
Breast Cancer Res. 2013 Mar 08;15(2):R21
pubmed: 23497505
JAMA. 2012 Apr 4;307(13):1383-93
pubmed: 22474202
Br J Cancer. 2006 Apr 10;94(7):1051-6
pubmed: 16538221
Lancet. 2016 May 14;387(10032):2008-16
pubmed: 26969090
Oncotarget. 2016 Jun 28;7(26):40767-40780
pubmed: 27004404
Lancet Oncol. 2012 Dec;13(12):1225-33
pubmed: 23168362
Lancet. 2011 Aug 27;378(9793):771-84
pubmed: 21802721