Protection of HT22 neuronal cells against chemically-induced ferroptosis by catechol estrogens: protein disulfide isomerase as a mechanistic target.

Publisher: Nature Publishing Group Country of Publication: England NLM ID: 101563288 Publication Model: Electronic Cited Medium: Internet ISSN: 2045-2322 (Electronic) Linking ISSN: 20452322 NLM ISO Abbreviation: Sci Rep Subsets: MEDLINE

Original Publication: London : Nature Publishing Group, copyright 2011-

Ferroptosis*/drug effects ; Protein Disulfide-Isomerases*/metabolism ; Neurons*/metabolism ; Neurons*/drug effects ; Estrogens, Catechol*/metabolism ; Estrogens, Catechol*/pharmacology ; Reactive Oxygen Species*/metabolism; Animals ; Mice ; Cell Line ; Lipid Peroxidation/drug effects ; Carbolines

Ferroptosis is a form of regulated cell death, characterized by excessive iron-dependent lipid peroxidation. Biochemically, ferroptosis can be selectively induced by erastin through glutathione depletion or through inhibition of glutathione peroxidase 4 by RSL3, which leads to accumulation of cytotoxic lipid reactive oxygen species (ROS). Protein disulfide isomerase (PDI) was recently shown to mediate erastin/RSL3-induced ferroptosis and thus also become a new target for protection against chemically-induced ferroptosis. The present study aims to identify endogenous compounds that can protect against erastin/RSL3-induced ferroptotic cell death. We find that 2-hydroxyestrone, 2-hydroxyestradiol, 4-hydroxyestrone and 4-hydroxyestradiol, four major endogenous catechol estrogens, are effective inhibitors of PDI, and can strongly protect against chemically-induced ferroptotic cell death in cultured HT22 mouse hippocampal neuronal cells. The CETSA assay showed that these catechol estrogens can bind to PDI in live cells. PDI knockdown attenuates the protective effect of these catechol estrogens against chemically-induced ferroptosis. Mechanistically, inhibition of PDI's catalytic activity by catechol estrogens abrogates erastin/RSL3-induced dimerization of nitric oxide synthase, thereby preventing the subsequent accumulation of cellular nitric oxide, ROS and lipid-ROS, and ultimately ferroptotic cell death. In addition, joint treatment of cells with catechol estrogens also abrogates erastin/RSL3-induced upregulation of nitric oxide synthase protein levels, which also contributes to the cytoprotective effect of the catechol estrogens. In conclusion, the present study demonstrates that the catechol estrogens are protectors of HT22 neuronal cells against chemically-induced ferroptosis, and inhibition of PDI's catalytic activity by these estrogens contributes to a novel, estrogen receptor-independent mechanism of cytoprotection.
(© 2024. The Author(s).)

Int J Mol Sci. 2023 Jun 08;24(12):. (PMID: 37373068)
Biochemistry. 2024 Apr 16;63(8):984-999. (PMID: 38569593)
J Biochem. 1981 Mar;89(3):889-900. (PMID: 7287643)
Cancer Cell. 2003 Mar;3(3):285-96. (PMID: 12676586)
Sci Rep. 2020 Apr 29;10(1):7283. (PMID: 32350290)
Biochem J. 2000 Feb 15;346 Pt 1:1-8. (PMID: 10657232)
Cancer Treat Rev. 2023 Jun;117:102569. (PMID: 37146385)
Cell. 2022 Jul 7;185(14):2401-2421. (PMID: 35803244)
Cell Death Discov. 2021 Jul 26;7(1):193. (PMID: 34312370)
Free Radic Biol Med. 2020 May 20;152:175-185. (PMID: 32165281)
Curr Drug Metab. 2002 Jun;3(3):321-49. (PMID: 12083324)
EMBO J. 1987 Mar;6(3):643-9. (PMID: 3034602)
Carcinogenesis. 1998 Oct;19(10):1821-7. (PMID: 9806165)
Acta Biochim Biophys Sin (Shanghai). 2023 May 30;55(5):853-865. (PMID: 37249331)
Biochem Biophys Res Commun. 2016 Aug 26;477(3):495-502. (PMID: 27317486)
Trends Biochem Sci. 1994 Aug;19(8):331-6. (PMID: 7940678)
Arch Biochem Biophys. 1998 Dec 1;360(1):105-12. (PMID: 9826435)
Cell Commun Signal. 2024 Apr 2;22(1):205. (PMID: 38566107)
J Mol Neurosci. 2022 Sep;72(9):1797-1808. (PMID: 35727524)
Front Cell Dev Biol. 2020 Sep 17;8:586578. (PMID: 33043019)
Genes Dev. 2018 May 1;32(9-10):602-619. (PMID: 29802123)
Cell Death Differ. 2022 Mar;29(3):467-480. (PMID: 35075250)
Nat Protoc. 2014 Sep;9(9):2100-22. (PMID: 25101824)
Front Pharmacol. 2022 Aug 29;13:910292. (PMID: 36105219)
Oxid Med Cell Longev. 2021 Jun 28;2021:5523516. (PMID: 34257804)
Neurobiol Dis. 2016 Oct;94:169-78. (PMID: 27189756)
Free Radic Biol Med. 2019 Mar;133:130-143. (PMID: 30268886)
Front Pharmacol. 2018 Nov 22;9:1371. (PMID: 30524291)
J Am Chem Soc. 2014 Mar 26;136(12):4551-6. (PMID: 24592866)
J Biol Chem. 1988 Nov 5;263(31):16218-24. (PMID: 2846539)
Sci Rep. 2024 Feb 15;14(1):3803. (PMID: 38360841)
Autophagy. 2021 Sep;17(9):2054-2081. (PMID: 32804006)
Cell. 2014 Jan 16;156(1-2):317-331. (PMID: 24439385)
Philos Trans R Soc Lond B Biol Sci. 2013 Mar 25;368(1617):20110403. (PMID: 23530257)
Biochem Biophys Res Commun. 1993 Oct 15;196(1):280-6. (PMID: 7692850)
Connect Tissue Res. 2014 Oct-Dec;55(5-6):367-77. (PMID: 25111192)
Curr Top Microbiol Immunol. 2017;403:143-170. (PMID: 28204974)
Cell Commun Signal. 2024 Sep 6;22(1):431. (PMID: 39243059)
Redox Biol. 2023 Jun;62:102703. (PMID: 37087975)
Nat Cell Biol. 2014 Dec;16(12):1180-91. (PMID: 25402683)
Trends Cell Biol. 2016 Mar;26(3):165-176. (PMID: 26653790)
Biochem Biophys Res Commun. 1987 Feb 13;142(3):919-24. (PMID: 3827906)
Endocrinology. 2006 Sep;147(9):4132-50. (PMID: 16728493)
Eur J Pharmacol. 2017 Apr 5;800:107-117. (PMID: 28219710)
Pharmacol Ther. 1993 Feb-Mar;57(2-3):237-57. (PMID: 8361994)
Elife. 2014 May 20;3:e02523. (PMID: 24844246)
Cell. 2017 Oct 5;171(2):273-285. (PMID: 28985560)
J Med Chem. 2023 Jul 13;66(13):8339-8381. (PMID: 37377342)
J Biol Chem. 2015 Nov 20;290(47):28097-28106. (PMID: 26400084)
Biochim Biophys Acta. 2008 Apr;1783(4):549-56. (PMID: 18191641)
Cell Death Discov. 2021 Oct 5;7(1):276. (PMID: 34611144)
J Biol Chem. 1994 Oct 7;269(40):24550-2. (PMID: 7929125)
J Nutr Biochem. 2015 May;26(5):549-55. (PMID: 25725506)
Mol Cell Biol. 2022 Jun 16;42(6):e0052221. (PMID: 35499331)
Biochem Biophys Res Commun. 2017 Jul 22;489(2):164-170. (PMID: 28549585)
Lipids. 1995 Feb;30(2):141-6. (PMID: 7769970)
Cell. 2012 May 25;149(5):1060-72. (PMID: 22632970)

KQTD2016053117035204 Shenzhen Peacock Plan; ZDSYS20190902093417963 Shenzhen Key Laboratory of Steroid Drug Discovery and Development; 81630096 National Natural Science Foundation of China; SZBL2019062801007 Shenzhen Bay Laboratory

Keywords: Catechol estrogens; Cytoprotective action; Lipid reactive oxygen species; Nitric oxide; Nitric oxide synthase; Protein disulfide isomerase; Reactive oxygen species

EC 5.3.4.1 (Protein Disulfide-Isomerases)
0 (Estrogens, Catechol)
0 (Reactive Oxygen Species)
0 (RSL3 compound)
0 (Carbolines)

Date Created: 20241014 Date Completed: 20241014 Latest Revision: 20241018

20241018

PMC11473836

10.1038/s41598-024-74742-5

39402104