Gochujang suppresses cell survival and changes reactive oxygen species metabolism in colorectal cancer cells

  • Eun-Bi Seo Department of Food Science and Human Nutrition, Jeonbuk National University, Jeonju, Republic of Korea
  • So-Min Oh Department of Food Science and Human Nutrition, Jeonbuk National University, Jeonju, Republic of Korea
  • Anna Han Department of Food Science and Human Nutrition, Jeonbuk National University
Keywords: Gochujang, Korean fermented food, K-food, Colorectal cancer cell, Anti-cancer, Mechanism, Reactive oxygen species, Apoptosis, Autophagy, Migration, Cell cycle, CRC

Abstract

There is a significant global increase in colorectal cancer (CRC) among young adults. Gochujang, one of the signature Korean traditional fermented foods, contains various bioactive compounds and has multiple health-beneficial effects, including anticancer effects; however, the detailed cellular and molecular mechanisms of its anticancer outcomes are not fully understood. The objective of the present study was to investigate the detailed underlying anticancer mechanisms of Gochujang in CRC cells. Gochujang was extracted with 80% ethanol, and total polyphenol contents (9.9 ± 1.63 mgGAE/g) and total flavonoid contents (0.14 ± 0.07 mgQE/g) of Gochujang extract (GE) were evaluated. GE significantly suppressed cell viability, migration, and colony formation in CRC cells. Also, GE increased the cell cycle arrest-related protein p21 level, whereas it decreased cell cycle progression-associated proteins, such as p-Rb. Moreover, GE markedly elevated the levels of proapoptotic proteins (e.g. Bim and c-PARP), while it downregulated antiapoptotic protein expressions (e.g. Bcl-2 and Bcl-xL). GE also altered the expression of the autophagy-involved proteins. Furthermore, GE strongly reduced the expression of major antioxidant enzymes and increased the reactive oxygen species (ROS) generation in CRC cells, causing an imbalance of ROS metabolism. In conclusion, this study demonstrated that Gochujang exerts anticancer effects in CRC cells by inhibiting cell proliferation, increasing cell death, and interrupting ROS metabolism.

Downloads

Download data is not yet available.

References


1.
Jung KW, Won YJ, Kang MJ, Kong HJ, Im JS, Seo HG. Prediction of cancer incidence and mortality in Korea, 2022. Cancer Res Treat 2022; 54(2): 345–51. doi: 10.4143/crt.2022.179


2.
Kim MH, Park S, Yi N, Kang B, Park IJ. Colorectal cancer mortality trends in the era of cancer survivorship in Korea: 2000–2020. Ann Coloproctol 2022; 38(5): 343–52. doi: 10.3393/ac.2022.00535.0076


3.
Siegel RL, Torre LA, Soerjomataram I, Hayes RB, Bray F, Weber TK, et al. Global patterns and trends in colorectal cancer incidence in young adults. Gut 2019; 68(12): 2179–85. doi: 10.1136/gutjnl-2019-319511


4.
Kim HJ, Hann HJ, Hong SN, Kim KH, Ahn IM, Song JY, et al. Incidence and natural course of inflammatory bowel disease in Korea, 2006–2012: a nationwide population-based study. Inflamm Bowel Dis 2015; 21(3): 623–30. doi: 10.1097/MIB.0000000000000313


5.
Daniali M, Nikfar S, Abdollahi M. An overview of interventions for constipation in adults. Expert Rev Gastroenterol Hepatol 2020; 14(8): 721–32. doi: 10.1080/17474124.2020.1781617


6.
Sohn DK, Kim MJ, Park Y, Suh M, Shin A, Lee HY, et al. The Korean guideline for colorectal cancer screening. J Korean Med Assoc 2015; 58(5): 420–32. doi: 10.5124/jkma.2015.58.5.420


7.
Khil H, Kim SM, Hong S, Gil HM, Cheon E, Lee DH, et al. Time trends of colorectal cancer incidence and associated lifestyle factors in South Korea. Sci Rep 2021; 11(1): 2413. doi: 10.1038/s41598-021-81877-2


8.
Murphy N, Moreno V, Hughes DJ, Vodicka L, Vodicka P, Aglago EK, et al. Lifestyle and dietary environmental factors in colorectal cancer susceptibility. Mol Aspects Med 2019; 69: 2–9. doi: 10.1016/j.mam.2019.06.005


9.
Chan DS, Lau R, Aune D, Vieira R, Greenwood DC, Kampman E, et al. Red and processed meat and colorectal cancer incidence: meta-analysis of prospective studies. PLoS One 2011; 6(6): e20456. doi: 10.1371/journal.pone.0020456


10.
Vieira AR, Abar L, Chan DSM, Vingeliene S, Polemiti E, Stevens C, et al. Foods and beverages and colorectal cancer risk: a systematic review and meta-analysis of cohort studies, an update of the evidence of the WCRF-AICR Continuous Update Project. Ann Oncol 2017; 28(8): 1788–802. doi: 10.1093/annonc/mdx171


11.
Demeyer D, Mertens B, De Smet S, Ulens M. Mechanisms linking colorectal cancer to the consumption of (processed) red meat: a review. Crit Rev Food Sci Nutr 2016; 56(16): 2747–66. doi: 10.1080/10408398.2013.873886


12.
Pietrzyk Ł. Food properties and dietary habits in colorectal cancer prevention and development. Int J Food Prop 2017; 20(10): 2323–43. doi: 10.1080/10942912.2016.1236813


13.
Macharia JM, Mwangi RW, Rozmann N, Zsolt K, Varjas T, Uchechukwu PO, et al. Medicinal plants with anti-colorectal cancer bioactive compounds: potential game-changers in colorectal cancer management. Biomed Pharmacother 2022; 153: 113383. doi: 10.1016/j.biopha.2022.113383


14.
Guerra AR, Duarte MF, Duarte IF. _targeting tumor metabolism with plant-derived natural products: emerging trends in cancer therapy. J Agric Food Chem 2018; 66(41): 10663–85. doi: 10.1021/acs.jafc.8b04104


15.
Cerella C, Radogna F, Dicato M, Diederich M. Natural compounds as regulators of the cancer cell metabolism. Int J Cell Biol 2013; 2013: 639401. doi: 10.1155/2013/639401


16.
Zeng H, Hamlin SK, Safratowich BD, Cheng WH, Johnson LK. Superior inhibitory efficacy of butyrate over propionate and acetate against human colon cancer cell proliferation via cell cycle arrest and apoptosis: linking dietary fiber to cancer prevention. Nutr Res 2020; 83: 63–72. doi: 10.1016/j.nutres.2020.08.009


17.
Yin Q, Chen H, Ma RH, Zhang YY, Liu MM, Thakur K, et al. Ginsenoside CK induces apoptosis of human cervical cancer HeLa cells by regulating autophagy and endoplasmic reticulum stress. Food Funct 2021; 12(12): 5301–16. doi: 10.1039/d1fo00348h


18.
Al-Oqail MM. Anticancer efficacies of Krameria lappacea extracts against human breast cancer cell line (MCF-7): role of oxidative stress and ROS generation. Saudi Pharm J 2021; 29(3): 244–51. doi: 10.1016/j.jsps.2021.01.008


19.
Kang SW. Role of reactive oxygen species in cell death pathways. Hanyang Med Rev 2013; 33(2): 77–82. doi: 10.7599/hmr.2013.33.2.77


20.
Choi I. Reactive oxygen species and cancer. Hanyang Med Rev 2013; 33(2): 118–22. doi: 10.7599/hmr.2013.33.2.118


21.
Hayes JD, Dinkova-Kostova AT, Tew KD. Oxidative stress in cancer. Cancer Cell 2020; 38(2): 167–97. doi: 10.1016/j.ccell.2020.06.001


22.
Tafani M, Sansone L, Limana F, Arcangeli T, De Santis E, Polese M, et al. The interplay of reactive oxygen species, hypoxia, inflammation, and sirtuins in cancer initiation and progression. Oxid Med Cell Longev 2016; 2016: 3907147. doi: 10.1155/2016/3907147


23.
Afrin S, Giampieri F, Forbes-Hernandez TY, Gasparrini M, Amici A, Cianciosi D, et al. Manuka honey synergistically enhances the chemopreventive effect of 5-fluorouracil on human colon cancer cells by inducing oxidative stress and apoptosis, altering metabolic phenotypes and suppressing metastasis ability. Free Radic Biol Med 2018; 126: 41–54. doi: 10.1016/j.freeradbiomed.2018.07.014


24.
Arfin S, Jha NK, Jha SK, Kesari KK, Ruokolainen J, Roychoudhury S, et al. Oxidative stress in cancer cell metabolism. Antioxidants (Basel) 2021; 10(5): 642. doi: 10.3390/antiox10050642


25.
Lee EJ, Edward OC, Seo EB, Mun EG, Jeong SJ, Ha G, et al. Gochujang ameliorates hepatic inflammation by improving dysbiosis of gut microbiota in high-fat diet-induced obese mice. Microorganisms 2023; 11(4): 911. doi: 10.3390/microorganisms11040911


26.
Kwon S-H, Shon M-Y. Antioxidant and anticarcinogenic effects of traditional doenjang during maturation periods. Korean J Food Preserv 2004; 11: 461–7.


27.
Mun E-G, Kim B, Kim E-Y, Lee H-J, Kim Y, Park Y, et al. Research trend in traditional fermented foods focused on health functional evaluation. J Korean Soc Food Sci Nutr 2018; 47(4): 373–86. doi: 10.3746/jkfn.2018.47.4.373


28.
Park JE, Han A, Mun EG, Cha YS. A traditional Korean fermented food, Gochujang exerts anti-hypertensive effects, regardless of its high salt content by regulating renin-angiotensin-aldosterone system in SD rats. Heliyon 2024; 10(9): e30451. doi: 10.1016/j.heliyon.2024.e30451


29.
Lee E-J, Song J, Park C-H, Mun E-G, Wang J, Han A, et al. Soy sauce lowers body weight and fat mass in high-fat diet-induced obese rats. J Med Food 2023; 26(11): 858–67. doi: 10.1089/jmf.2022.K.0125


30.
Kim NY, Kim KA, Yang HJ, Jeong SJ, Han A, Cha YS. Comparison of the laxative effects of Korean Gochujang containing different microbiota on loperamide-induced constipation in ICR mice. Food Funct 2023; 14(16): 7615–30. doi: 10.1039/d2fo04111a


31.
Chang M-I, Kim J-Y, Kim U-S, Baek S-H. Antioxidant, tyrosinase inhibitory, and anti-proliferative activities of Gochujang added with Cheonggukjang powder made from sword bean. Korean J Food Sci Technol 2013; 45(2): 221–6. doi: 10.9721/kjfst.2013.45.2.221


32.
Jung KO, Park SY, Park KY. Longer aging time increases the anticancer and antimetastatic properties of doenjang. Nutrition 2006; 22(5): 539–45. doi: 10.1016/j.nut.2005.11.007


33.
Kim SY, Lee KB, Cho YH, Jeong DY, Yang HJ, Ryu MS, et al. Inhibitory effect of the extract of Cheonggukjang fermented with Bacillus amyloliquefaciens SCGB 1 on LPS-induced inflammation and inflammatory diseases. J Korean Soc Food Sci Nutr 2020; 49(7): 659–67. doi: 10.3746/jkfn.2020.49.7.659


34.
Lee SM, Chang HC. Growth-inhibitory effect of the solar salt-doenjang on cancer cells, AGS and HT-29. J Korean Soc Food Sci Nutr 2009; 38(12): 1664–71. doi: 10.3746/jkfn.2009.38.12.1664


35.
Mahoro P, Moon HJ, Yang HJ, Kim KA, Cha YS. Protective effect of Gochujang on inflammation in a DSS-induced colitis rat model. Foods 2021; 10(5): 1072. doi: 10.3390/foods10051072


36.
Lee H, Song J, Chung S, Cha Y-S, Han A. Gochujang elicits anti-obesity effects by increasing capsaicin-independent brown adipogenesis and thermogenesis in high-fat diet induced obese mice. J Funct Foods 2023; 111: 105886. doi: 10.1016/j.jff.2023.105886


37.
Song H-S, Kim Y-M, Lee K-T. Antioxidant and anticancer activities of traditional Kochujang added with garlic porridge. J Life Sci 2008; 18: 1140–6. doi: 10.5352/JLS.2008.18.8.1140


38.
Ehiobu JM, Idamokoro ME, Afolayan AJ. Phytochemical content and antioxidant potential of leaf extracts of Citrus limon (L.) Osbeck collected in the Eastern Cape Province, South Africa. S Afr J Bot 2021; 141: 480–6. doi: 10.1016/j.sajb.2021.06.001


39.
Singleton VL, Orthofer R, Lamuela-Raventós RM. Analysis of total phenols and other oxidation substrates and antioxidants by means of folin-ciocalteu reagent. Methods Enzymol 1999; 299: 152–78. doi: 10.1016/S0076-6879(99)99017-1


40.
Zhishen J, Mengcheng T, Jianming W. The determination of flavonoid contents in mulberry and their scavenging effects on superoxide radicals. Food Chem 1999; 64: 555–9. doi: 10.1016/S0308-8146(98)00102-2


41.
Matthews HK, Bertoli C, de Bruin RAM. Cell cycle control in cancer. Nat Rev Mol Cell Biol 2022; 23(1): 74–88. doi: 10.1038/s41580-021-00404-3


42.
Elmore S. Apoptosis: a review of programmed cell death. Toxicol Pathol 2007; 35(4): 495–516. doi: 10.1080/01926230701320337


43.
Yang Z, Klionsky DJ. An overview of the molecular mechanism of autophagy. Curr Top Microbiol Immunol 2009; 335: 1–32. doi: 10.1007/978-3-642-00302-8_1


44.
Yuan J, Che S, Zhang L, Ruan Z. Reparative effects of ethanol-induced intestinal barrier injury by flavonoid luteolin via MAPK/NF-kappaB/MLCK and Nrf2 signaling pathways. J Agric Food Chem 2021; 69(14): 4101–10. doi: 10.1021/acs.jafc.1c00199


45.
Li Z, Mao L, Yu B, Liu H, Zhang Q, Bian Z, et al. GB7 acetate, a galbulimima alkaloid from Galbulimima belgraveana, possesses anticancer effects in colorectal cancer cells. J Pharm Anal 2022; 12(2): 339–49. doi: 10.1016/j.jpha.2021.06.007


46.
Wu Q, Deng J, Fan D, Duan Z, Zhu C, Fu R, et al. Ginsenoside Rh4 induces apoptosis and autophagic cell death through activation of the ROS/JNK/p53 pathway in colorectal cancer cells. Biochem Pharmacol 2018; 148: 64–74. doi: 10.1016/j.bcp.2017.12.004


47.
Berg KCG, Eide PW, Eilertsen IA, Johannessen B, Bruun J, Danielsen SA, et al. Multi-omics of 34 colorectal cancer cell lines – a resource for biomedical studies. Mol Cancer 2017; 16(1): 116. doi: 10.1186/s12943-017-0691-y


48.
Sveen A, Bruun J, Eide PW, Eilertsen IA, Ramirez L, Murumagi A, et al. Colorectal cancer consensus molecular subtypes translated to preclinical models uncover potentially _targetable cancer cell dependencies. Clin Cancer Res 2018; 24(4): 794–806. doi: 10.1158/1078-0432.CCR-17-1234


49.
DeMaio L, Rouhanizadeh M, Reddy S, Sevanian A, Hwang J, Hsiai TK. Oxidized phospholipids mediate occludin expression and phosphorylation in vascular endothelial cells. Am J Physiol Heart Circ Physiol 2006; 290(2): H674–83. doi: 10.1152/ajpheart.00554.2005


50.
Raghunath A, Sundarraj K, Nagarajan R, Arfuso F, Bian J, Kumar AP, et al. Antioxidant response elements: discovery, classes, regulation and potential applications. Redox Biol 2018; 17: 297–314. doi: 10.1016/j.redox.2018.05.002


51.
Khan I, Kang SC. Apoptotic activity of Lactobacillus plantarum DGK-17-fermented soybean seed extract in human colon cancer cells via ROS-JNK signaling pathway. J Food Sci 2017; 82(6): 1475–83. doi: 10.1111/1750-3841.13732
Published
2024-10-21
How to Cite
Seo E.-B., Oh S.-M., & Han A. (2024). <em>Gochujang</em&gt; suppresses cell survival and changes reactive oxygen species metabolism in colorectal cancer cells. Food & Nutrition Research, 68. https://doi.org/10.29219/fnr.v68.10844
Section
Original Articles