Reversal of obesity-driven aggressiveness of endometrial cancer by metformin.
Metformin
endometrial cancer
metabolomics
obesity
proliferation
Journal
American journal of cancer research
ISSN: 2156-6976
Titre abrégé: Am J Cancer Res
Pays: United States
ID NLM: 101549944
Informations de publication
Date de publication:
2019
2019
Historique:
received:
11
09
2019
accepted:
20
09
2019
entrez:
14
11
2019
pubmed:
14
11
2019
medline:
14
11
2019
Statut:
epublish
Résumé
Obesity and diabetes are associated with increased risk and worse outcomes for endometrial cancer. Metformin is a widely prescribed generic drug for the treatment of type II diabetes and metabolic syndrome and may also have anti-tumorigenic effects. Thus, we assessed the metabolic anti-tumorigenic effects of metformin in (1) human endometrial cancer cell lines under varying glucose concentrations, and (2) a novel genetically engineered mouse model of endometrioid endometrial cancer under obese and lean conditions. The effects of metformin on cytotoxicity, apoptosis, cell cycle progression, and the AMPK/mTOR/S6 and MAPK pathways were assessed in ECC-1 and Ishikawa cells under low, normal and high glucose conditions. The impact of metformin treatment on tumor growth under obese and lean conditions was evaluated using a novel LKB1 Hypoglycemic conditions significantly enhanced the sensitivity of the cells to metformin in regards to its anti-proliferative and apoptotic effects, as compared to hyperglycemic and normal glucose conditions. Metformin inhibited tumor growth in both the obese and lean mice, which metformin-induced inhibition of tumor progression in obese mice was significantly greater than in lean mice. Metabolomic profiling in endometrial cancer tissues revealed significant differences between obese- and lean-mice. Enhanced energy metabolism was seen in obese- The obese state promoted tumor aggressiveness in the LKB1
Sections du résumé
BACKGROUND
BACKGROUND
Obesity and diabetes are associated with increased risk and worse outcomes for endometrial cancer. Metformin is a widely prescribed generic drug for the treatment of type II diabetes and metabolic syndrome and may also have anti-tumorigenic effects. Thus, we assessed the metabolic anti-tumorigenic effects of metformin in (1) human endometrial cancer cell lines under varying glucose concentrations, and (2) a novel genetically engineered mouse model of endometrioid endometrial cancer under obese and lean conditions.
METHODS
METHODS
The effects of metformin on cytotoxicity, apoptosis, cell cycle progression, and the AMPK/mTOR/S6 and MAPK pathways were assessed in ECC-1 and Ishikawa cells under low, normal and high glucose conditions. The impact of metformin treatment on tumor growth under obese and lean conditions was evaluated using a novel LKB1
RESULTS
RESULTS
Hypoglycemic conditions significantly enhanced the sensitivity of the cells to metformin in regards to its anti-proliferative and apoptotic effects, as compared to hyperglycemic and normal glucose conditions. Metformin inhibited tumor growth in both the obese and lean mice, which metformin-induced inhibition of tumor progression in obese mice was significantly greater than in lean mice. Metabolomic profiling in endometrial cancer tissues revealed significant differences between obese- and lean-mice. Enhanced energy metabolism was seen in obese-
CONCLUSIONS
CONCLUSIONS
The obese state promoted tumor aggressiveness in the LKB1
Types de publication
Journal Article
Langues
eng
Pagination
2170-2193Subventions
Organisme : NIDDK NIH HHS
ID : P30 DK056350
Pays : United States
Organisme : NCI NIH HHS
ID : R37 CA226969
Pays : United States
Informations de copyright
AJCR Copyright © 2019.
Déclaration de conflit d'intérêts
None.
Références
Sci Rep. 2017 Aug 18;7(1):8803
pubmed: 28821813
Cancer Res. 2008 Feb 1;68(3):759-66
pubmed: 18245476
Gynecol Oncol. 2010 Jan;116(1):92-8
pubmed: 19822355
Clin Cancer Res. 2006 Nov 1;12(21):6373-8
pubmed: 17085648
J Clin Oncol. 2013 Jul 10;31(20):2607-18
pubmed: 23733771
J Natl Cancer Inst. 2013 Mar 6;105(5):342-9
pubmed: 23297041
Eur J Gynaecol Oncol. 2007;28(2):95-7
pubmed: 17479668
Obstet Gynecol Surv. 2014 Aug;69(8):477-89
pubmed: 25144611
Proc Natl Acad Sci U S A. 2011 Feb 22;108(8):3270-5
pubmed: 21289278
J Obstet Gynaecol Res. 2012 Aug;38(8):1077-85
pubmed: 22540333
Oncotarget. 2017 Jun 29;8(38):63551-63561
pubmed: 28969010
Front Oncol. 2017 Sep 14;7:216
pubmed: 28959684
Pharmacol Res. 2018 May;131:75-86
pubmed: 29580896
J Dent Res. 2018 Jul;97(7):759-766
pubmed: 29533734
Endocr Relat Cancer. 2015 Dec;22(6):919-32
pubmed: 26362676
Gynecol Oncol. 2014 Jan;132(1):236-40
pubmed: 24189334
PLoS One. 2017 Jan 23;12(1):e0170318
pubmed: 28114390
Cancer Discov. 2011 Jul;1(2):170-85
pubmed: 21984976
Nat Rev Endocrinol. 2014 Mar;10(3):143-56
pubmed: 24393785
Oncotarget. 2017 Jan 31;8(5):8622-8632
pubmed: 28052008
Cancer Cell Int. 2014 Jun 16;14:53
pubmed: 24966801
Diabetes Care. 2012 Feb;35(2):299-304
pubmed: 22266734
Gynecol Oncol. 2015 Sep;138(3):668-75
pubmed: 26135947
Gynecol Oncol. 2016 Dec;143(3):466-471
pubmed: 27745917
J Clin Oncol. 2012 Jul 20;30(21):2593-600
pubmed: 22564993
Gynecol Oncol. 2016 Jan;140(1):184-90
pubmed: 26524722
PLoS One. 2014 Sep 25;9(9):e108444
pubmed: 25254953
Cancer Causes Control. 2011 Aug;22(8):1163-71
pubmed: 21688131
Cancer. 2014 Oct 1;120(19):2986-95
pubmed: 24917306
Adv Exp Med Biol. 2017;943:3-46
pubmed: 27910063
J Biol Chem. 2014 Mar 14;289(11):7884-96
pubmed: 24492615
J Immunol. 2019 Feb 15;202(4):1265-1286
pubmed: 30659108
Endocr Relat Cancer. 2010 Jun 01;17(2):351-60
pubmed: 20228137
Cancer Epidemiol Biomarkers Prev. 2008 Apr;17(4):921-9
pubmed: 18398032
Anal Chem. 2009 Aug 15;81(16):6656-67
pubmed: 19624122
Best Pract Res Clin Endocrinol Metab. 2008 Aug;22(4):659-69
pubmed: 18971125
Gynecol Oncol. 2010 Feb;116(2):187-94
pubmed: 19903572
Horm Mol Biol Clin Investig. 2015 Aug;23(2):47-57
pubmed: 26167982
Gynecol Oncol. 2014 Feb;132(2):438-42
pubmed: 24269517
Cancer Prev Res (Phila). 2014 Jan;7(1):54-64
pubmed: 24196830
Endocr Relat Cancer. 2015 Aug;22(4):577-91
pubmed: 26045471
Nature. 2002 Sep 12;419(6903):162-7
pubmed: 12226664
CA Cancer J Clin. 2019 Jan;69(1):7-34
pubmed: 30620402
Gastroenterology. 2001 Apr;120(5):1263-70
pubmed: 11266389
Biochem Biophys Res Commun. 2010 Jul 2;397(3):537-42
pubmed: 20573602
Cancer Res. 2014 Jan 1;74(1):15-23
pubmed: 24322983
Annu Rev Med. 2015;66:17-29
pubmed: 25386929
Annu Rev Pathol. 2016 May 23;11:421-49
pubmed: 27193454
Mol Metab. 2016 Apr 23;5(7):506-526
pubmed: 27408776
Clin Cancer Res. 2010 Mar 15;16(6):1695-700
pubmed: 20215559
BMJ. 2005 Jun 4;330(7503):1304-5
pubmed: 15849206
FASEB J. 2009 Feb;23(2):586-604
pubmed: 18945875
Asian Pac J Cancer Prev. 2015;16(1):221-5
pubmed: 25640355
Nat Rev Cancer. 2009 Aug;9(8):563-75
pubmed: 19629071
Adv Exp Med Biol. 2017;943:211-241
pubmed: 27910069
Gynecol Oncol. 2017 Apr;145(1):200-207
pubmed: 28040204
Diabetes Care. 2006 Feb;29(2):254-8
pubmed: 16443869
Oncol Lett. 2016 Nov;12(5):3626-3632
pubmed: 27900046
Eur J Obstet Gynecol Reprod Biol. 2009 Aug;145(2):195-9
pubmed: 19501448
Cell Cycle. 2012 Aug 1;11(15):2782-92
pubmed: 22809961
Diabetes Care. 2009 Sep;32(9):1620-5
pubmed: 19564453
Cancer Discov. 2012 Sep;2(9):778-90
pubmed: 22926251
Proc Natl Acad Sci U S A. 2009 Mar 24;106(12):4834-9
pubmed: 19261849
Cancer Sci. 2011 Dec;102(12):2272-7
pubmed: 21910784
Int J Gynecol Cancer. 2007 Mar-Apr;17(2):441-6
pubmed: 17362320
PLoS One. 2012;7(6):e38812
pubmed: 22701716
Genes Dev. 2000 Apr 15;14(8):994-1004
pubmed: 10783170
Gynecol Oncol. 2014 Apr;133(1):90-7
pubmed: 24680597
Elife. 2014 May 13;3:e02242
pubmed: 24843020
J Clin Oncol. 2016 Dec 10;34(35):4277-4283
pubmed: 27903152
Cancer Prev Res (Phila). 2017 Jan;10(1):1-13
pubmed: 27965288
Am J Obstet Gynecol. 2011 Dec;205(6):518-25
pubmed: 21802066
Oncotarget. 2017 Sep 8;8(67):110965-110982
pubmed: 29340030
Endocr Relat Cancer. 2008 Sep;15(3):833-9
pubmed: 18469156
Oncotarget. 2015 Sep 15;6(27):23548-60
pubmed: 26172303
Pharmacogenomics. 2008 Apr;9(4):383-97
pubmed: 18384253
Am J Obstet Gynecol. 2016 Jun;214(6):689.e1-689.e17
pubmed: 26829507
Breast Cancer Res Treat. 2010 Sep;123(2):333-44
pubmed: 20204498
Pharmacol Res. 2016 Nov;113(Pt A):675-685
pubmed: 27720766
Expert Rev Mol Diagn. 2010 May;10(4):509-19
pubmed: 20465505
Nat Rev Cancer. 2011 Nov 24;11(12):886-95
pubmed: 22113164
Oncotarget. 2016 Aug 9;7(32):52364-52374
pubmed: 27429042
J Clin Oncol. 2016 Dec 10;34(35):4225-4230
pubmed: 27903150
Cancer. 2014 Nov 15;120(22):3457-68
pubmed: 25042259
Mol Cancer Ther. 2013 Dec;12(12):2847-56
pubmed: 24077915
PLoS One. 2013 Apr 19;8(4):e61537
pubmed: 23620761
BMC Cancer. 2017 Mar 29;17(1):232
pubmed: 28356082
N Engl J Med. 2003 Apr 24;348(17):1625-38
pubmed: 12711737
Gynecol Oncol. 2012 May;125(2):458-69
pubmed: 22252099
Methods Mol Biol. 2018;1752:1-9
pubmed: 29564757
Dis Model Mech. 2010 Mar-Apr;3(3-4):181-93
pubmed: 20142330
Nat Rev Clin Oncol. 2011 May;8(5):261-71
pubmed: 21221135
Oncogene. 1998 Jul 9;17(1):1-12
pubmed: 9671308
Cancer Res. 2010 Mar 15;70(6):2465-75
pubmed: 20215500
Nature. 2013 May 2;497(7447):67-73
pubmed: 23636398
Cancer Res. 2008 Jul 15;68(14):5619-27
pubmed: 18632614
Trends Endocrinol Metab. 2013 Sep;24(9):469-80
pubmed: 23773243
Gynecol Oncol. 2014 Apr;133(1):28-32
pubmed: 24680588
Trends Mol Med. 2007 Jun;13(6):252-9
pubmed: 17452018
Mol Cancer Ther. 2012 May;11(5):1082-91
pubmed: 22402126
Crit Rev Oncol Hematol. 2016 Sep;105:73-83
pubmed: 27378194