Journal of Veterinary Science

The Korean Society of Veterinary Science (대한수의학회)
권호 표지
DOI QR코드

DOI QR Code

Epigallocatechin-3-gallate suppresses hemin-aggravated colon carcinogenesis through Nrf2-inhibited mitochondrial reactive oxygen species accumulation

  • Seok, Ju Hyung (College of Veterinary Medicine and Veterinary Medicine Center, Chungbuk National University) ;
  • Kim, Dae Hyun (College of Veterinary Medicine and Veterinary Medicine Center, Chungbuk National University) ;
  • Kim, Hye Jih (College of Veterinary Medicine and Veterinary Medicine Center, Chungbuk National University) ;
  • Jo, Hang Hyo (College of Veterinary Medicine and Veterinary Medicine Center, Chungbuk National University) ;
  • Kim, Eun Young (Korea Food Culture Promotion Association) ;
  • Jeong, Jae-Hwang (Department of Biotechnology and Biomedicine, Chungbuk Provincial University) ;
  • Park, Young Seok (Department of Neurosurgery, Chungbuk National University Hospital) ;
  • Lee, Sang Hun (Departments of Biochemistry, Soonchunhyang University College of Medicine) ;
  • Kim, Dae Joong (College of Veterinary Medicine and Veterinary Medicine Center, Chungbuk National University) ;
  • Nam, Sang Yoon (College of Veterinary Medicine and Veterinary Medicine Center, Chungbuk National University) ;
  • Lee, Beom Jun (College of Veterinary Medicine and Veterinary Medicine Center, Chungbuk National University) ;
  • Lee, Hyun Jik (College of Veterinary Medicine and Veterinary Medicine Center, Chungbuk National University)
  • Received : 2022.04.06
  • Accepted : 2022.07.18
  • Published : 2022.09.30
Download PDF
⟨ Previous Next ⟩

Abstract

Background: Previous studies have presented evidence to support the significant association between red meat intake and colon cancer, suggesting that heme iron plays a key role in colon carcinogenesis. Epigallocatechin-3-gallate (EGCG), the major constituent of green tea, exhibits anti-oxidative and anti-cancer effects. However, the effect of EGCG on red meat-associated colon carcinogenesis is not well understood. Objectives: We aimed to investigate the regulatory effects of hemin and EGCG on colon carcinogenesis and the underlying mechanism of action. Methods: Hemin and EGCG were treated in Caco2 cells to perform the water-soluble tetrazolium salt-1 assay, lactate dehydrogenase release assay, reactive oxygen species (ROS) detection assay, real-time quantitative polymerase chain reaction and western blot. We investigated the regulatory effects of hemin and EGCG on an azoxymethane (AOM) and dextran sodium sulfate (DSS)-induced colon carcinogenesis mouse model. Results: In Caco2 cells, hemin increased cell proliferation and the expression of cell cycle regulatory proteins, and ROS levels. EGCG suppressed hemin-induced cell proliferation and cell cycle regulatory protein expression as well as mitochondrial ROS accumulation. Hemin increased nuclear factor erythroid-2-related factor 2 (Nrf2) expression, but decreased Keap1 expression. EGCG enhanced hemin-induced Nrf2 and antioxidant gene expression. Nrf2 inhibitor reversed EGCG reduced cell proliferation and cell cycle regulatory protein expression. In AOM/DSS mice, hemin treatment induced hyperplastic changes in colon tissues, inhibited by EGCG supplementation. EGCG reduced the hemin-induced numbers of total aberrant crypts and malondialdehyde concentration in the AOM/DSS model. Conclusions: We demonstrated that EGCG reduced hemin-induced proliferation and colon carcinogenesis through Nrf2-inhibited mitochondrial ROS accumulation.

Keywords

Acknowledgement

This research was supported by National R&D Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Science, ICT & Future Planning (NRF-2021R1C1C1009595) and "Regional Innovation Strategy (RIS)" through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (MOE, 2021RIS-001).

References

  1. Seiwert N, Heylmann D, Hasselwander S, Fahrer J. Mechanism of colorectal carcinogenesis triggered by heme iron from red meat. Biochim Biophys Acta Rev Cancer. 2020;1873(1):188334. https://doi.org/10.1016/j.bbcan.2019.188334
  2. Gamage SM, Dissabandara L, Lam AK, Gopalan V. The role of heme iron molecules derived from red and processed meat in the pathogenesis of colorectal carcinoma. Crit Rev Oncol Hematol. 2018;126:121-128. https://doi.org/10.1016/j.critrevonc.2018.03.025
  3. Wiseman M. The second World Cancer Research Fund/American Institute for Cancer Research expert report. Food, nutrition, physical activity, and the prevention of cancer: a global perspective. Proc Nutr Soc. 2008;67(3):253-256. https://doi.org/10.1017/S002966510800712X
  4. Bastide NM, Pierre FH, Corpet DE. Heme iron from meat and risk of colorectal cancer: a meta-analysis and a review of the mechanisms involved. Cancer Prev Res (Phila). 2011;4(2):177-184. https://doi.org/10.1158/1940-6207.CAPR-10-0113
  5. Sesink AL, Termont DS, Kleibeuker JH, Van der Meer R. Red meat and colon cancer: the cytotoxic and hyperproliferative effects of dietary heme. Cancer Res 1999;59(22):5704-5709.
  6. Pierre F, Tache S, Petit CR, Van der Meer R, Corpet DE. Meat and cancer: haemoglobin and haemin in a low-calcium diet promote colorectal carcinogenesis at the aberrant crypt stage in rats. Carcinogenesis. 2003;24(10):1683-1690. https://doi.org/10.1093/carcin/bgg130
  7. Fiorito V, Chiabrando D, Petrillo S, Bertino F, Tolosano E. The multifaceted role of heme in cancer. Front Oncol. 2020;9:1540. https://doi.org/10.3389/fonc.2019.01540
  8. Sodring M, Oostindjer M, Egelandsdal B, Paulsen JE. Effects of hemin and nitrite on intestinal tumorigenesis in the A/J Min/+ mouse model. PLoS One. 2015;10(4):e0122880. https://doi.org/10.1371/journal.pone.0122880
  9. Sesink AL, Termont DS, Kleibeuker JH, Van Der Meer R. Red meat and colon cancer: dietary haem, but not fat, has cytotoxic and hyperproliferative effects on rat colonic epithelium. Carcinogenesis. 2000;21(10):1909-1915. https://doi.org/10.1093/carcin/21.10.1909
  10. Cheng Z, Li Y. What is responsible for the initiating chemistry of iron-mediated lipid peroxidation: an update. Chem Rev. 2007;107(3):748-766. https://doi.org/10.1021/cr040077w
  11. Gaschler MM, Stockwell BR. Lipid peroxidation in cell death. Biochem Biophys Res Commun. 2017;482(3):419-425. https://doi.org/10.1016/j.bbrc.2016.10.086
  12. Tappel A. Heme of consumed red meat can act as a catalyst of oxidative damage and could initiate colon, breast and prostate cancers, heart disease and other diseases. Med Hypotheses. 2007;68(3):562-564. https://doi.org/10.1016/j.mehy.2006.08.025
  13. Kim HS, Quon MJ, Kim JA. New insights into the mechanisms of polyphenols beyond antioxidant properties; lessons from the green tea polyphenol, epigallocatechin 3-gallate. Redox Biol. 2014;2:187-195. https://doi.org/10.1016/j.redox.2013.12.022
  14. Eng QY, Thanikachalam PV, Ramamurthy S. Molecular understanding of epigallocatechin gallate (EGCG) in cardiovascular and metabolic diseases. J Ethnopharmacol. 2018;210:296-310. https://doi.org/10.1016/j.jep.2017.08.035
  15. Kuriyama S, Shimazu T, Ohmori K, Kikuchi N, Nakaya N, Nishino Y, et al. Green tea consumption and mortality due to cardiovascular disease, cancer, and all causes in Japan: the Ohsaki study. JAMA. 2006;296(10):1255-1265. https://doi.org/10.1001/jama.296.10.1255
  16. Meng Q, Velalar CN, Ruan R. Regulating the age-related oxidative damage, mitochondrial integrity, and antioxidative enzyme activity in Fischer 344 rats by supplementation of the antioxidant epigallocatechin-3-gallate. Rejuvenation Res. 2008;11(3):649-660. https://doi.org/10.1089/rej.2007.0645
  17. Na HK, Surh YJ. Modulation of Nrf2-mediated antioxidant and detoxifying enzyme induction by the green tea polyphenol EGCG. Food Chem Toxicol. 2008;46(4):1271-1278. https://doi.org/10.1016/j.fct.2007.10.006
  18. La X, Zhang L, Li Z, Li H, Yang Y. (-)-Epigallocatechin gallate (EGCG) enhances the sensitivity of colorectal cancer cells to 5-FU by inhibiting GRP78/NF-κB/miR-155-5p/MDR1 pathway. J Agric Food Chem. 2019;67(9):2510-2518. https://doi.org/10.1021/acs.jafc.8b06665
  19. Lee HJ, Jung YH, Choi GE, Ko SH, Lee SJ, Lee SH, et al. BNIP3 induction by hypoxia stimulates FASN-dependent free fatty acid production enhancing therapeutic potential of umbilical cord blood-derived human mesenchymal stem cells. Redox Biol. 2017;13:426-443. https://doi.org/10.1016/j.redox.2017.07.004
  20. Kruger C, Zhou Y. Red meat and colon cancer: a review of mechanistic evidence for heme in the context of risk assessment methodology. Food Chem Toxicol. 2018;118:131-153. https://doi.org/10.1016/j.fct.2018.04.048
  21. Fiorito V, Allocco AL, Petrillo S, Gazzano E, Torretta S, Marchi S, et al. The heme synthesis-export system regulates the tricarboxylic acid cycle flux and oxidative phosphorylation. Cell Reports. 2021;35(11):109252. https://doi.org/10.1016/j.celrep.2021.109252
  22. Hooda J, Cadinu D, Alam MM, Shah A, Cao TM, Sullivan LA, et al. Enhanced heme function and mitochondrial respiration promote the progression of lung cancer cells. PLoS One. 2013;8(5):e63402. https://doi.org/10.1371/journal.pone.0063402
  23. Hill M, Pereira V, Chauveau C, Zagani R, Remy S, Tesson L, et al. Heme oxygenase-1 inhibits rat and human breast cancer cell proliferation: mutual cross inhibition with indoleamine 2,3-dioxygenase. FASEB J. 2005;19(14):1957-1968. https://doi.org/10.1096/fj.05-3875com
  24. IJssennagger N, Rijnierse A, de Wit N, Jonker-Termont D, Dekker J, Muller M, et al. Dietary haem stimulates epithelial cell turnover by downregulating feedback inhibitors of proliferation in murine colon. Gut. 2012;61(7):1041-1049. https://doi.org/10.1136/gutjnl-2011-300239
  25. Ijssennagger N, Rijnierse A, de Wit NJ, Boekschoten MV, Dekker J, Schonewille A, et al. Dietary heme induces acute oxidative stress, but delayed cytotoxicity and compensatory hyperproliferation in mouse colon. Carcinogenesis. 2013;34(7):1628-1635. https://doi.org/10.1093/carcin/bgt084
  26. Sabharwal SS, Schumacker PT. Mitochondrial ROS in cancer: initiators, amplifiers or an Achilles' heel? Nat Rev Cancer. 2014;14(11):709-721. https://doi.org/10.1038/nrc3803
  27. Namslauer I, Brzezinski P. A mitochondrial DNA mutation linked to colon cancer results in proton leaks in cytochrome c oxidase. Proc Natl Acad Sci U S A. 2009;106(9):3402-3407. https://doi.org/10.1073/pnas.0811450106
  28. Idelchik MD, Begley U, Begley TJ, Melendez JA. Mitochondrial ROS control of cancer. Semin Cancer Biol. 2017;47:57-66. https://doi.org/10.1016/j.semcancer.2017.04.005
  29. Luo KW, Xia J, Cheng BH, Gao HC, Fu LW, Luo XL. Tea polyphenol EGCG inhibited colorectal-cancer-cell proliferation and migration via downregulation of STAT3. Gastroenterol Rep (Oxf ). 2021;9(1):59-70. https://doi.org/10.1093/gastro/goaa072
  30. Cia D, Vergnaud-Gauduchon J, Jacquemot N, Doly M. Epigallocatechin gallate (EGCG) prevents H2O2-induced oxidative stress in primary rat retinal pigment epithelial cells. Curr Eye Res. 2014;39(9):944-952. https://doi.org/10.3109/02713683.2014.885532
  31. Osburn WO, Kensler TW. Nrf2 signaling: an adaptive response pathway for protection against environmental toxic insults. Mutat Res. 2008;659(1-2):31-39. https://doi.org/10.1016/j.mrrev.2007.11.006
  32. Kim YC, Masutani H, Yamaguchi Y, Itoh K, Yamamoto M, Yodoi J. Hemin-induced activation of the thioredoxin gene by Nrf2. A differential regulation of the antioxidant responsive element by a switch of its binding factors. J Biol Chem. 2001;276(21):18399-18406. https://doi.org/10.1074/jbc.M100103200
  33. Jang HY, Hong OY, Chung EY, Park KH, Kim JS. Roles of JNK/Nrf2 pathway on hemin-induced heme oxygenase-1 activation in MCF-7 human breast cancer cells. Medicina (Kaunas). 2020;56(6):268. https://doi.org/10.3390/medicina56060268
  34. Boyle JJ, Johns M, Lo J, Chiodini A, Ambrose N, Evans PC, et al. Heme induces heme oxygenase 1 via Nrf2: role in the homeostatic macrophage response to intraplaque hemorrhage. Arterioscler Thromb Vasc Biol. 2011;31(11):2685-2691. https://doi.org/10.1161/ATVBAHA.111.225813
  35. Han XD, Zhang YY, Wang KL, Huang YP, Yang ZB, Liu Z. The involvement of Nrf2 in the protective effects of (-)-epigallocatechin-3-gallate (EGCG) on NaAsO2-induced hepatotoxicity. Oncotarget. 2017;8(39):65302-65312. https://doi.org/10.18632/oncotarget.18582
  36. Sun W, Liu X, Zhang H, Song Y, Li T, Liu X, et al. Epigallocatechin gallate upregulates NRF2 to prevent diabetic nephropathy via disabling KEAP1. Free Radic Biol Med. 2017;108:840-857. https://doi.org/10.1016/j.freeradbiomed.2017.04.365
  37. Baumel-Alterzon S, Katz LS, Brill G, Garcia-Ocana A, Scott DK. Nrf2: the master and captain of beta cell fate. Trends Endocrinol Metab. 2021;32(1):7-19. https://doi.org/10.1016/j.tem.2020.11.002
  38. Pierre FH, Santarelli RL, Allam O, Tache S, Naud N, Gueraud F, et al. Freeze-dried ham promotes azoxymethane-induced mucin-depleted foci and aberrant crypt foci in rat colon. Nutr Cancer. 2010;62(5):567-573. https://doi.org/10.1080/01635580903532408
  39. Radulescu S, Brookes MJ, Salgueiro P, Ridgway RA, McGhee E, Anderson K, et al. Luminal iron levels govern intestinal tumorigenesis after Apc loss in vivo. Cell Reports. 2016;17(10):2805-2807. https://doi.org/10.1016/j.celrep.2016.10.028
  40. Rada P, Rojo AI, Offergeld A, Feng GJ, Velasco-Martin JP, Gonzalez-Sancho JM, et al. WNT-3A regulates an Axin1/NRF2 complex that regulates antioxidant metabolism in hepatocytes. Antioxid Redox Signal. 2015;22(7):555-571. https://doi.org/10.1089/ars.2014.6040
  41. Kim H, Yin K, Falcon DM, Xue X. The interaction of Hemin and Sestrin2 modulates oxidative stress and colon tumor growth. Toxicol Appl Pharmacol. 2019;374:77-85. https://doi.org/10.1016/j.taap.2019.04.025
  42. Kwak TW, Park SB, Kim HJ, Jeong YI, Kang DH. Anticancer activities of epigallocatechin-3-gallate against cholangiocarcinoma cells. Onco Targets Ther. 2016;10:137-144 https://doi.org/10.2147/OTT.S112364