Nrf2 depletion enhanced curcumin therapy effect in gastric cancer by inducing the excessive accumulation of ROS.

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-

NF-E2-Related Factor 2*/metabolism ; NF-E2-Related Factor 2*/genetics ; Curcumin*/pharmacology ; Curcumin*/therapeutic use ; Stomach Neoplasms*/drug therapy ; Stomach Neoplasms*/metabolism ; Stomach Neoplasms*/pathology ; Stomach Neoplasms*/genetics ; Reactive Oxygen Species*/metabolism ; Cell Proliferation*/drug effects; Humans ; Animals ; Cell Line, Tumor ; Mice ; Xenograft Model Antitumor Assays ; Signal Transduction/drug effects ; Oxidative Stress/drug effects ; Mice, Nude ; Cell Movement/drug effects ; Kelch-Like ECH-Associated Protein 1/metabolism

Gastric cancer (GC) is the most common malignant tumor of the gastrointestinal tract and currently has a poor clinical outcome. Turmeric's rhizome contains a polyphenolic component called curcumin (Cur), which has been demonstrated to inhibit a variety of tumor cells, such as pancreatic, colon, lung and gastric cancers. However, it remains to be elucidated how Cur functions in GC and what molecular processes underlie it. Here, Cur showed a stronger inhibitory effect on GC cells AGS and HGC27. In addition, Cur's inhibition of GC cells growth was accompanied by increased ROS production, triggering of the Keap1-Nrf2 signaling pathway, and increased transcription of its downstream antioxidant genes HO-1, GCLM, and NQO1. However, when a ROS scavenger NAC was used, the inhibitory effect of Cur on GC cells was reversed. Nuclear factor erythroid 2-related factor 2 (Nrf2) is overexpressed or activated in cancers to shield cancer cells from oxidative damage by responding to oxidative stress (OS). Cur has been found to act as an activator of Nrf2. Notably, compared with Nrf2 knockdown and Cur alone, the combination of the two dramatically increased Cur-induced ROS overaccumulation and inhibition of GC cells proliferation, migration, and invasive abilities. Consistent with in vitro experiments, Cur combined with Nrf2 knockdown significantly inhibited tumor growth in nude mice transplanted with AGS cells. Therefore, we concluded that Nrf2 depletion enhanced Cur therapy effect in GC by inducing the excessive accumulation of ROS, indicating that this is a promising treatment strategy.
Competing Interests: Declarations. Competing interests: The authors declare no competing interests. Statements of accordance and arrive guidelines: Accordance: We confirmed that all experiments in this study were performed in accordance with the relevant guidelines and regulations. Arrive: All the procedure of the study is followed by the ARRIVE guidelines. Ethics statement: Animal experiments were reviewed and approved by the Animal Care and Welfare Committee of the Affiliated Hospital of Qingdao University (ethics number AHQU-MAL20230825).
(© 2024. The Author(s).)

Free Radic Biol Med. 2020 May 20;152:175-185. (PMID: 32165281)
Am J Chin Med. 2018;46(6):1357-1368. (PMID: 30149755)
Open Life Sci. 2021 Sep 06;16(1):937-949. (PMID: 34553074)
Toxicol Appl Pharmacol. 2024 Mar;484:116842. (PMID: 38307257)
Mol Cell. 2012 Oct 26;48(2):158-67. (PMID: 23102266)
Life Sci. 2021 Nov 1;284:119942. (PMID: 34506835)
Thorac Cancer. 2021 Apr;12(8):1219-1230. (PMID: 33656766)
Chem Res Toxicol. 2018 Feb 19;31(2):88-96. (PMID: 29228771)
Cell Biochem Funct. 2024 Jan;42(1):e3911. (PMID: 38269517)
J Asian Nat Prod Res. 2015;17(1):56-63. (PMID: 25492214)
Cancer Cell. 2018 Jul 9;34(1):21-43. (PMID: 29731393)
J Nat Prod. 2020 Mar 27;83(3):770-803. (PMID: 32162523)
Cancer Manag Res. 2020 May 21;12:3795-3806. (PMID: 32547215)
Cancers (Basel). 2020 Dec 26;13(1):. (PMID: 33375248)
Antioxidants (Basel). 2019 Oct 26;8(11):. (PMID: 31717825)
Nucleic Acids Res. 2023 Jan 6;51(D1):D587-D592. (PMID: 36300620)
Cell Death Differ. 2023 Jul;30(7):1771-1785. (PMID: 37210578)
Exp Mol Med. 2020 Feb;52(2):192-203. (PMID: 32060354)
J Clin Oncol. 2006 Jun 20;24(18):2903-9. (PMID: 16782930)
Mater Sci Eng C Mater Biol Appl. 2017 Aug 1;77:1316-1326. (PMID: 28532009)
Biomolecules. 2019 Nov 13;9(11):. (PMID: 31766246)
Nucleic Acids Res. 2008 Jun;36(10):3420-35. (PMID: 18445632)
Phytother Res. 2010 Apr;24(4):500-2. (PMID: 19927272)
Med Sci Monit. 2015 Sep 27;21:2893-9. (PMID: 26410168)
Oncol Rep. 2017 Jun;37(6):3459-3466. (PMID: 28498433)
CA Cancer J Clin. 2021 May;71(3):209-249. (PMID: 33538338)
Crit Rev Food Sci Nutr. 2020;60(6):887-939. (PMID: 30632782)
Biochem J. 1996 Jan 1;313 ( Pt 1):17-29. (PMID: 8546679)
Redox Biol. 2015 Aug;5:124-139. (PMID: 25912168)
PLoS One. 2022 Jan 18;17(1):e0261370. (PMID: 35041678)
Cochrane Database Syst Rev. 2017 Aug 29;8:CD004064. (PMID: 28850174)
Frontline Gastroenterol. 2020 Jul 30;12(4):322-331. (PMID: 34249318)
Annu Rev Pharmacol Toxicol. 2013;53:401-26. (PMID: 23294312)
Front Pharmacol. 2022 Sep 02;13:990475. (PMID: 36120367)
Oxid Med Cell Longev. 2023 Jan 14;2023:6896790. (PMID: 36691638)
Mech Ageing Dev. 2019 Jan;177:37-45. (PMID: 29604323)
Cancer Discov. 2018 May;8(5):537-555. (PMID: 29653955)
Tumour Biol. 2017 Jul;39(7):1010428317714626. (PMID: 28671042)
Chem Rev. 2009 Jul;109(7):3012-43. (PMID: 19422222)
Lancet. 2020 Aug 29;396(10251):635-648. (PMID: 32861308)
Naunyn Schmiedebergs Arch Pharmacol. 2009 Jan;379(1):47-60. (PMID: 18716759)
J Biol Chem. 2013 Aug 9;288(32):23009-20. (PMID: 23801334)
Antioxidants (Basel). 2020 Dec 04;9(12):. (PMID: 33291560)
Redox Biol. 2013 Jan 18;1:45-9. (PMID: 24024136)
Nutr Cancer. 2023;75(2):726-733. (PMID: 36346025)
Heliyon. 2021 Feb;7(2):e06350. (PMID: 33655086)
Trends Mol Med. 2004 Nov;10(11):549-57. (PMID: 15519281)
Chem Biol Interact. 2014 Dec 5;224:164-75. (PMID: 25452175)
J Cell Physiol. 2019 Aug;234(8):12537-12550. (PMID: 30623450)
Drug Des Devel Ther. 2021 Nov 02;15:4503-4525. (PMID: 34754179)
Blood. 2009 Jan 8;113(2):462-9. (PMID: 18815282)
Semin Cancer Biol. 2022 May;80:73-86. (PMID: 32088363)
Int J Mol Sci. 2022 Jul 26;23(15):. (PMID: 35897820)
Int J Mol Sci. 2019 Apr 12;20(8):. (PMID: 31013694)
Nat Rev Cancer. 2012 Jul 19;12(8):564-71. (PMID: 22810811)
Biomed Pharmacother. 2024 Nov;180:117404. (PMID: 39307117)
Redox Biol. 2015 Aug;5:347-357. (PMID: 26122399)
Cell Death Discov. 2022 Oct 26;8(1):427. (PMID: 36289191)

2021-zyym29 Qingdao traditional Chinese medicine science and technology project; 202103030554 Shandong medical and health science and technology development plan project; Y-HR2018-185 Beijing Xisike Clinical Oncology Research Foundation

Keywords: Curcumin; Gastric cancer; Oxidative stress; ROS; The Keap1-Nrf2 signaling pathway

0 (NF-E2-Related Factor 2)
IT942ZTH98 (Curcumin)
0 (Reactive Oxygen Species)
0 (NFE2L2 protein, human)
0 (Kelch-Like ECH-Associated Protein 1)

Date Created: 20241203 Date Completed: 20241203 Latest Revision: 20241207

20241209

PMC11615379

10.1038/s41598-024-81375-1

39627516