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Background: Polycystic ovary syndrome (PCOS), which is often accompanied by insulin resistance, is closely related to increased apoptosis of ovarian granulosa cells. LNK is an important regulator of the insulin signaling pathway. When insulin binds to the receptor, the PI3K/AKT/FOXO signaling pathway is activated, and FOXO translocates from the nucleus to the cytoplasm, thereby inhibiting the expression of pro-apoptotic genes.

Methods: Granulosa cells were collected from PCOS patients to investigate the relationship between LNK, cell apoptosis and insulin resistance. KGN cells underwent LNK overexpression/silence and insulin stimulation. The AKT/FOXO3 pathway was studied by western blot and immunofluorescence. LNK knockout mice were used to investigate the effect of LNK on the pathogenesis of PCOS.

Results: The level of LNK was higher in PCOS group than control group. LNK was positively correlated with granulosa cell apoptosis and insulin resistance, and negatively correlated with oocyte maturation rate. LNK overexpression in KGN cells inhibited insulin-induced AKT/FOXO3 signaling pathway, causing nucleus translocation of FOXO3 and promoting granulosa cell apoptosis. LNK knockout partially restored estrous cycle and improved glucose metabolism in PCOS mice.

Conclusions: LNK was closely related to insulin resistance and apoptosis of granulosa cells via the AKT/FOXO3 pathway. LNK knockout partially restored estrous cycle and improved glucose metabolism in PCOS mice, suggesting LNK might become a potential biological target for the clinical treatment of PCOS.

Titel:	LNK promotes granulosa cell apoptosis in PCOS via negatively regulating insulin-stimulated AKT-FOXO3 pathway.
Autor/in / Beteiligte Person:	Tan, M ; Cheng, Y ; Zhong, X ; Yang, D ; Jiang, S ; Ye, Y ; Ding, M ; Guan, G ; Zhao, X
Link:	Full Text Finder (Volltext)
Zeitschrift:	Aging, Jg. 13 (2021-01-20), Heft 3, S. 4617-4633
Veröffentlichung:	Albany, NY : Impact Journals, LLC, 2021
Medientyp:	academicJournal
ISSN:	1945-4589 (electronic)
DOI:	10.18632/aging.202421
Schlagwort:	Adaptor Proteins, Signal Transducing metabolism Adult Animals Female Humans In Vitro Techniques Insulin Resistance Mice Mice, Knockout Polycystic Ovary Syndrome metabolism Signal Transduction Young Adult Adaptor Proteins, Signal Transducing genetics Apoptosis genetics Forkhead Box Protein O3 metabolism Granulosa Cells metabolism Insulin metabolism Polycystic Ovary Syndrome genetics Proto-Oncogene Proteins c-akt metabolism
Sonstiges:	Nachgewiesen in: MEDLINE Sprachen: English Publication Type: Journal Article; Research Support, Non-U.S. Gov't Language: English [Aging (Albany NY)] 2021 Jan 20; Vol. 13 (3), pp. 4617-4633. <i>Date of Electronic Publication: </i>2021 Jan 20. MeSH Terms: Adaptor Proteins, Signal Transducing / genetics ; Apoptosis / genetics ; Forkhead Box Protein O3 / metabolism ; Granulosa Cells / metabolism ; Insulin / metabolism ; Polycystic Ovary Syndrome / genetics ; Proto-Oncogene Proteins c-akt / *metabolism ; Adaptor Proteins, Signal Transducing / metabolism ; Adult ; Animals ; Female ; Humans ; In Vitro Techniques ; Insulin Resistance ; Mice ; Mice, Knockout ; Polycystic Ovary Syndrome / metabolism ; Signal Transduction ; Young Adult References: J Clin Invest. 2010 Jun;120(6):2058-69. (PMID: 20458146) ; Cochrane Database Syst Rev. 2019 Dec 17;12:CD013505. (PMID: 31845767) ; Oncogene. 2008 Apr 7;27(16):2312-9. (PMID: 18391973) ; Development. 2020 Jan 17;147(2):. (PMID: 31852686) ; Oncogene. 2005 Nov 14;24(50):7410-25. (PMID: 16288288) ; Aging (Albany NY). 2020 Sep 10;12(17):17150-17166. (PMID: 32911464) ; J Clin Endocrinol Metab. 2019 May 1;104(5):1841-1854. (PMID: 30544235) ; Trends Endocrinol Metab. 2019 Mar;30(3):150-162. (PMID: 30712978) ; Mol Cell Endocrinol. 2000 May 25;163(1-2):49-52. (PMID: 10963873) ; J Clin Endocrinol Metab. 2013 Sep;98(9):E1491-500. (PMID: 23846817) ; Oxid Med Cell Longev. 2017;2017:3494289. (PMID: 28894507) ; Endocrinology. 2016 Oct;157(10):3709-3718. (PMID: 27459314) ; J Clin Endocrinol Metab. 1998 Sep;83(9):3078-82. (PMID: 9745406) ; PLoS Genet. 2010 Mar 19;6(3):e1000881. (PMID: 20333234) ; Trends Biochem Sci. 2014 Apr;39(4):159-69. (PMID: 24630600) ; Semin Cancer Biol. 2018 Jun;50:65-76. (PMID: 29309929) ; Fertil Steril. 2004 Jan;81(1):19-25. (PMID: 14711538) ; Nat Genet. 2009 Jun;41(6):677-87. (PMID: 19430479) ; Endocrine. 2016 Sep;53(3):823-30. (PMID: 27060006) ; Nat Genet. 2012 Sep;44(9):1020-5. (PMID: 22885925) ; Hum Reprod Update. 2020 Jan 1;26(1):103-117. (PMID: 31867675) ; Nat Commun. 2019 May 20;10(1):2230. (PMID: 31110180) ; Hum Reprod Update. 2008 Jul-Aug;14(4):367-78. (PMID: 18499708) ; Int J Biol Sci. 2017 Jul 6;13(7):815-827. (PMID: 28808415) ; Biochem Pharmacol. 2011 Nov 15;82(10):1391-402. (PMID: 21723852) ; Front Endocrinol (Lausanne). 2019 Mar 01;10:93. (PMID: 30881341) ; Clin Endocrinol (Oxf). 1993 Sep;39(3):351-5. (PMID: 8222298) ; Endocrinology. 2018 Jan 1;159(1):297-309. (PMID: 29029022) ; J Cell Mol Med. 2020 Oct;24(20):11874-11882. (PMID: 32869942) ; Hum Mol Genet. 2011 Jun 1;20(11):2273-84. (PMID: 21378095) ; Biochem Biophys Res Commun. 2017 Aug 19;490(2):91-97. (PMID: 28526415) ; Diabetes Care. 2010 Jan;33 Suppl 1:S62-9. (PMID: 20042775) ; J Clin Invest. 2012 Jun;122(6):2079-91. (PMID: 22546852) ; Diabetes Care. 2004 Jun;27(6):1487-95. (PMID: 15161807) ; Cell. 1985 Apr;40(4):747-58. (PMID: 2859121) ; Reprod Sci. 2015 Mar;22(3):271-7. (PMID: 25228632) ; Diabetologia. 1985 Jul;28(7):412-9. (PMID: 3899825) Contributed Indexing: Keywords: FOXO3; LNK; apoptosis; insulin resistance; polycystic ovary syndrome Substance Nomenclature: 0 (Adaptor Proteins, Signal Transducing) ; 0 (Forkhead Box Protein O3) ; 0 (Insulin) ; 0 (Lnk protein, mouse) ; 0 (SH2B3 protein, human) ; EC 2.7.11.1 (Proto-Oncogene Proteins c-akt) Entry Date(s): Date Created: 20210126 Date Completed: 20210816 Latest Revision: 20210816 Update Code: 20231215 PubMed Central ID: PMC7906173

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LNK promotes granulosa cell apoptosis in PCOS via negatively regulating insulin-stimulated AKT-FOXO3 pathway.