Involvement of AMP-activated Protein Kinase α/Nuclear Factor (Erythroid-derived 2) Like 2-iniatived Signaling Pathway in Cytoprotective Effects of Wasabi 6-(Methylsulfinyl) Hexyl Isothiocyanate

Overview

Journal J Cancer Prev

Specialty Oncology

Date 2022 Apr 14

PMID 35419303

Authors

Xuchi Pan

Kun Xie

Keyu Chen

Ziyu He

Kozue Sakao

De-Xing Hou

Affiliations

Soon will be listed here.

Abstract

6-(Methylsulfinyl) hexyl isothiocyanate (6-MSITC) is an active ingredient present in Wasabi, which is a popular pungent spice used in Japanese cuisine. Our previous studies suggested that the primary antioxidant activity of 6-MSITC may link to other biological activity. This study aimed to clarify how the antioxidant activity of 6-MSITC contributes to preventing overloaded lipid stress in hepatic cell model. HepG2 cells were treated with 6-MSITC at defined concentrations and times in normal medium or in combined fatty acids (CFA) medium, and the targeted proteins were detected by Western blotting. The kinetic data revealed that 6-MSITC activated AMP-activated protein kinase α (AMPKα) and nuclear factor (erythroid-derived 2) like 2 (Nrf2), and then enhanced the protein expression of Forkhead box protein O1 (FOXO1) and Sirtuin1 as well as that of the Nrf2 target proteins, NAD(P)H:quinone oxidoreductase 1 (NQO1) and heme oxygenase (HO-1). Furthermore, lipid metabolic stress was mimicked in HepG2 cells by overloading CFA. 6-MSITC significantly alleviated CFA-induced formation of thiobarbituric acid reactive substances and fat accumulation. Signaling analysis data revealed that 6-MSITC enhanced phosphorylation of AMPKα, upregulated the expression of Nrf2, NQO1, heme oxygenase 1, FOXO1, and Siruin1, and downregulated the expression of PPARα. Taken together, our results suggested that the AMPKα/Nrf2-mediated signaling pathways might be involved in the cytoprotective effects of Wasabi 6-MSITC against metabolic lipid stress.

Citing Articles

Methylsulfinyl Hexyl Isothiocyanate (6-MSITC) from Wasabi Is a Promising Candidate for the Treatment of Cancer, Alzheimer's Disease, and Obesity.

Bartkowiak-Wieczorek J, Malesza M, Malesza I, Hadada T, Winkler-Galicki J, Grzelak T Nutrients. 2024; 16(15).

PMID: 39125389 PMC: 11313713. DOI: 10.3390/nu16152509.

References

Cullinan S, Diehl J . PERK-dependent activation of Nrf2 contributes to redox homeostasis and cell survival following endoplasmic reticulum stress. J Biol Chem. 2004; 279(19):20108-17. DOI: 10.1074/jbc.M314219200. View

Zmijewski J, Banerjee S, Bae H, Friggeri A, Lazarowski E, Abraham E . Exposure to hydrogen peroxide induces oxidation and activation of AMP-activated protein kinase. J Biol Chem. 2010; 285(43):33154-33164. PMC: 2963401. DOI: 10.1074/jbc.M110.143685. View

Oowatari Y, Ogawa T, Katsube T, Iinuma K, Yoshitomi H, Gao M . Wasabi leaf extracts attenuate adipocyte hypertrophy through PPARγ and AMPK. Biosci Biotechnol Biochem. 2016; 80(8):1594-601. DOI: 10.1080/09168451.2016.1179093. View

Yamada-Kato T, Nagai M, Ohnishi M, Yoshida K . Inhibitory effects of wasabi isothiocyanates on chemical mediator release in RBL-2H3 rat basophilic leukemia cells. J Nutr Sci Vitaminol (Tokyo). 2012; 58(4):303-7. DOI: 10.3177/jnsv.58.303. View

Mosmann T . Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J Immunol Methods. 1983; 65(1-2):55-63. DOI: 10.1016/0022-1759(83)90303-4. View

Singh C, Chhabra G, Ndiaye M, Garcia-Peterson L, Mack N, Ahmad N . The Role of Sirtuins in Antioxidant and Redox Signaling. Antioxid Redox Signal. 2017; 28(8):643-661. PMC: 5824489. DOI: 10.1089/ars.2017.7290. View

Garcia D, Shaw R . AMPK: Mechanisms of Cellular Energy Sensing and Restoration of Metabolic Balance. Mol Cell. 2017; 66(6):789-800. PMC: 5553560. DOI: 10.1016/j.molcel.2017.05.032. View

Grahame Hardie D, Ross F, Hawley S . AMPK: a nutrient and energy sensor that maintains energy homeostasis. Nat Rev Mol Cell Biol. 2012; 13(4):251-62. PMC: 5726489. DOI: 10.1038/nrm3311. View

Velagapudi R, El-Bakoush A, Lepiarz I, Ogunrinade F, Olajide O . AMPK and SIRT1 activation contribute to inhibition of neuroinflammation by thymoquinone in BV2 microglia. Mol Cell Biochem. 2017; 435(1-2):149-162. PMC: 5632349. DOI: 10.1007/s11010-017-3064-3. View

10.

Huang C, Shiu S, Wu M, Chen W, Wang S, Lee H . Monacolin K affects lipid metabolism through SIRT1/AMPK pathway in HepG2 cells. Arch Pharm Res. 2013; 36(12):1541-51. DOI: 10.1007/s12272-013-0150-2. View

11.

Fuke Y, Hishinuma M, Namikawa M, Oishi Y, Matsuzaki T . Wasabi-derived 6-(methylsulfinyl)hexyl isothiocyanate induces apoptosis in human breast cancer by possible involvement of the NF-κB pathways. Nutr Cancer. 2014; 66(5):879-87. DOI: 10.1080/01635581.2014.916322. View

12.

Hou D, Fukuda M, Fujii M, Fuke Y . Transcriptional regulation of nicotinamide adenine dinucleotide phosphate: quinone oxidoreductase in murine hepatoma cells by 6-(methylsufinyl)hexyl isothiocyanate, an active principle of wasabi (Eutrema wasabi Maxim). Cancer Lett. 2000; 161(2):195-200. DOI: 10.1016/s0304-3835(00)00611-x. View

13.

Xie K, He X, Chen K, Sakao K, Hou D . Ameliorative effects and molecular mechanisms of vine tea on western diet-induced NAFLD. Food Funct. 2020; 11(7):5976-5991. DOI: 10.1039/d0fo00795a. View

14.

Yano S, Wu S, Sakao K, Hou D . Wasabi 6-(methylsulfinyl)hexyl isothiocyanate induces apoptosis in human colorectal cancer cells through p53-independent mitochondrial dysfunction pathway. Biofactors. 2018; . DOI: 10.1002/biof.1431. View

15.

Purushotham A, Xu Q, Li X . Systemic SIRT1 insufficiency results in disruption of energy homeostasis and steroid hormone metabolism upon high-fat-diet feeding. FASEB J. 2011; 26(2):656-67. PMC: 3290439. DOI: 10.1096/fj.11-195172. View

16.

Trio P, Fujisaki S, Tanigawa S, Hisanaga A, Sakao K, Hou D . DNA Microarray Highlights Nrf2-Mediated Neuron Protection Targeted by Wasabi-Derived Isothiocyanates in IMR-32 Cells. Gene Regul Syst Bio. 2016; 10:73-83. PMC: 4982521. DOI: 10.4137/GRSB.S39440. View

17.

Zhao L, Guo X, Wang O, Zhang H, Wang Y, Zhou F . Fructose and glucose combined with free fatty acids induce metabolic disorders in HepG2 cell: A new model to study the impacts of high-fructose/sucrose and high-fat diets in vitro. Mol Nutr Food Res. 2016; 60(4):909-21. DOI: 10.1002/mnfr.201500635. View

18.

Uto T, Fujii M, Hou D . Effects of 6-(methylsulfinyl)hexyl isothiocyanate on cyclooxygenase-2 expression induced by lipopolysaccharide, interferon-gamma and 12-O-tetradecanoylphorbol-13-acetate. Oncol Rep. 2006; 17(1):233-8. View

19.

Morroni F, Sita G, Tarozzi A, Cantelli-Forti G, Hrelia P . Neuroprotection by 6-(methylsulfinyl)hexyl isothiocyanate in a 6-hydroxydopamine mouse model of Parkinson׳s disease. Brain Res. 2014; 1589:93-104. DOI: 10.1016/j.brainres.2014.09.033. View

20.

Nita M, Grzybowski A . The Role of the Reactive Oxygen Species and Oxidative Stress in the Pathomechanism of the Age-Related Ocular Diseases and Other Pathologies of the Anterior and Posterior Eye Segments in Adults. Oxid Med Cell Longev. 2016; 2016:3164734. PMC: 4736974. DOI: 10.1155/2016/3164734. View