title: Metformin inhibits 17β-estradiol-induced epithelial-to-mesenchymal transition via βKlotho-related ERK1/2 signaling and AMPKα signaling in endometrial adenocarcinoma cells.
abstract: The potential role of metformin in treating endometrial cancer remains to be explored. The current study investigated the role of metformin in 17β-estradiol-induced epithelial-mesenchymal transition (EMT) in endometrial adenocarcinoma cells. We found that 17β-estradiol promoted proliferation and migration, attenuated apoptosis in both estrogen receptor (ER) positive and ER negative endometrial adenocarcinoma cells (Ishikawa and KLE cells, respectively). Metformin abolished 17β-estradiol-induced cell proliferation and reversed 17β-estradiol-induced EMT in Ishikawa cells. In addition, metformin increased the expression of βKlotho, a fibroblast growth factors (FGFs) coreceptor, and decreased ERK1/2 phosphorylation in both Ishikawa and KLE cells. Decreased expression of βKlotho was noted in human endometrial adenocarcinomas, and plasmid-driven expression of βKlotho in Ishikawa cells abolished 17β-estradiol-induced EMT via inhibiting ERK1/2 signaling. βKlotho expression and metformin show synergetic effects on the proliferation and the EMT in Ishikawa cells. Furthermore, we demonstrated that the anti-EMT effects of metformin could be partly abolished by introducing Compound C, a specific AMPKα signaling inhibitor. In conclusion, metformin abolishes 17β-estradiol-induced cell proliferation and EMT in endometrial adenocarcinoma cells by upregulating βKlotho expression, inhibiting ERK1/2 signaling, and activating AMPKα signaling. Our study provides novel mechanistic insight into the anti-tumor effects of metformin.
authors.affiliation: Department of Urology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong, People's Republic of China.
authors.forename: Zhao
authors.initials: Z
authors.lastname: Liu
authors.affiliation: Department of Obstetrics and Gynecology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong, People's Republic of China.
authors.forename: Shasha
authors.initials: S
authors.lastname: Qi
authors.affiliation: Department of Obstetrics and Gynecology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong, People's Republic of China.
authors.forename: Xingbo
authors.initials: X
authors.lastname: Zhao
authors.affiliation: Department of Obstetrics and Gynecology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong, People's Republic of China.
authors.forename: Mingjiang
authors.initials: M
authors.lastname: Li
authors.affiliation: Department of Urology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong, People's Republic of China.
authors.forename: Sentai
authors.initials: S
authors.lastname: Ding
authors.affiliation: Department of Urology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong, People's Republic of China.
authors.forename: Jiaju
authors.initials: J
authors.lastname: Lu
authors.affiliation: Department of Obstetrics and Gynecology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong, People's Republic of China.
authors.forename: Hui
authors.initials: H
authors.lastname: Zhang
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000230:Adenocarcinoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D000328:Adult; D017209:Apoptosis; D014408:Biomarkers, Tumor / Q000378:metabolism*; D002465:Cell Movement; D049109:Cell Proliferation; D016889:Endometrial Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D004717:Endometrium / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects*; D004958:Estradiol / Q000494:pharmacology*; D004967:Estrogens / Q000494:pharmacology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology; D000090265:Klotho Proteins; D008565:Membrane Proteins / Q000378:metabolism; D008687:Metformin / Q000494:pharmacology*; D008875:Middle Aged; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D010766:Phosphorylation; D011960:Receptors, Estrogen / Q000378:metabolism; D015398:Signal Transduction; D014407:Tumor Cells, Cultured
chemical_list: D014408:Biomarkers, Tumor; D004967:Estrogens; D007004:Hypoglycemic Agents; C538995:KLB protein, human; D008565:Membrane Proteins; D011960:Receptors, Estrogen; D004958:Estradiol; D008687:Metformin; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D055372:AMP-Activated Protein Kinases; C526180:PRKAA1 protein, human; D000090265:Klotho Proteins
keywords: 17β-estradiol; endometrial adenocarcinoma; epithelial-mesenchymal transition; metformin; βKlotho
references.citation: Oncotarget. 2015 Jan 20;6(2):1327-39
references.pmid: 25415225
references.citation: Gynecol Oncol. 2014 Feb;132(2):438-42
references.pmid: 24269517
references.citation: Mech Dev. 2000 Nov;98(1-2):115-9
references.pmid: 11044614
references.citation: Oncogene. 2015 Jun 4;34(23):3076-84
references.pmid: 25088204
references.citation: Eur J Pharmacol. 2013 Apr 5;705(1-3):96-108
references.pmid: 23499688
references.citation: J Pathol. 2010 Nov;222(3):261-70
references.pmid: 20814901
references.citation: Nat Cell Biol. 2012 Nov;14 (11):1212-22
references.pmid: 23086238
references.citation: Clin Cancer Res. 2014 May 15;20(10):2714-26
references.pmid: 24644001
references.citation: Nat Rev Endocrinol. 2014 Mar;10(3):143-56
references.pmid: 24393785
references.citation: Cell. 2009 Nov 25;139(5):871-90
references.pmid: 19945376
references.citation: J Biol Chem. 2007 Sep 14;282(37):26687-95
references.pmid: 17623664
references.citation: Int J Breast Cancer. 2012;2012:654698
references.pmid: 22295247
references.citation: J Cell Biol. 2006 Mar 27;172(7):973-81
references.pmid: 16567498
references.citation: Cancer Cell. 2010 Apr 13;17 (4):319-32
references.pmid: 20385358
references.citation: Mol Cell Endocrinol. 2013 Aug 25;376(1-2):60-9
references.pmid: 23419500
references.citation: Mol Cell Biochem. 2014 Jan;386(1-2):63-71
references.pmid: 24096736
references.citation: Gynecol Oncol. 2012 Aug;126(2):176-9
references.pmid: 22507532
references.citation: Mol Endocrinol. 2012 Sep;26(9):1521-30
references.pmid: 22734040
references.citation: Biotechnol Appl Biochem. 2012 May-Jun;59(3):262-7
references.pmid: 23586837
references.citation: Lancet. 2003 May 24;361(9371):1810-2
references.pmid: 12781553
references.citation: Cancer Res. 2008 Apr 1;68(7):2479-88
references.pmid: 18381457
references.citation: Clin Sci (Lond). 2012 Mar;122(6):253-70
references.pmid: 22117616
references.citation: Cancer Cell Int. 2014 Jun 16;14:53
references.pmid: 24966801
references.citation: Mol Cell Endocrinol. 2009 Feb 5;299(1):72-8
references.pmid: 19063940
references.citation: Oncotarget. 2015 Sep 29;6(29):27763-77
references.pmid: 26318034
references.citation: PLoS One. 2014 May 23;9(5):e98207
references.pmid: 24858012
references.citation: Lancet Oncol. 2015 Jun;16(6):686-94
references.pmid: 25981814
references.citation: Gynecol Oncol. 2006 Nov;103(2):623-30
references.pmid: 16806441
references.citation: Mol Cell. 2015 Apr 2;58(1):35-46
references.pmid: 25728771
references.citation: J Biol Chem. 2003 Jun 6;278(23 ):21113-23
references.pmid: 12665527
references.citation: J Clin Oncol. 2004 Apr 1;22(7):1242-52
references.pmid: 15051772
references.citation: Mod Pathol. 2008 Jul;21(7):912-23
references.pmid: 18487993
references.citation: J Clin Endocrinol Metab. 2011 Mar;96(3):808-16
references.pmid: 21190977
references.citation: Clin Cancer Res. 2016 Jan 1;22(1):259-67
references.pmid: 26373574
references.citation: J Clin Invest. 2009 Jun;119(6):1429-37
references.pmid: 19487819
references.citation: Clin Cancer Res. 2013 Mar 1;19(5):1094-105
references.pmid: 23319822
references.citation: PLoS One. 2013 Aug 02;8(8):e71583
references.pmid: 23936520
references.citation: Biochim Biophys Acta. 2009 Dec;1796(2):75-90
references.pmid: 19306912
references.citation: Diabetologia. 2007 Jul;50(7):1365-74
references.pmid: 17476474
references.citation: CA Cancer J Clin. 2014 Jan-Feb;64(1):9-29
references.pmid: 24399786
references.citation: Endocr Rev. 2001 Apr;22(2):153-83
references.pmid: 11294822
references.citation: Cell Cycle. 2010 Nov 15;9(22):4461-8
references.pmid: 21088486
references.citation: J Cell Sci. 2005 Mar 1;118(Pt 5):873-87
references.pmid: 15713751
references.citation: Cancer Res. 2015 Jun 1;75(11):2349-62
references.pmid: 25855378
references.citation: Clin Cancer Res. 2004 Aug 15;10(16):5546-53
references.pmid: 15328195
references.citation: Chem Res Toxicol. 2015 Apr 20;28(4):662-71
references.pmid: 25690688
references.citation: Diabetes Care. 2010 Jul;33(7):1674-85
references.pmid: 20587728
references.citation: Mol Hum Reprod. 2009 Oct;15(10 ):653-63
references.pmid: 19684091
references.citation: J Natl Cancer Inst. 2013 Mar 6;105(5):342-9
references.pmid: 23297041
references.citation: Gynecol Oncol. 2010 Jan;116(1):92-8
references.pmid: 19822355