Seed-derived peptide lunasin suppressed breast cancer cell growth by regulating inflammatory mediators, aromatase, and estrogen receptors

Chia-Chien Hsieh; Chi-Hao  Wu; Shih-Han  Peng; Chia-Hsin  Chang

doi:10.29219/fnr.v67.8991

Chia-Chien Hsieh Department of Biochemical Science & Technology, National Taiwan University, Taipei, Taiwan
Chi-Hao Wu School of Life Science, Undergraduate and Graduate Programs of Nutrition Science, National Taiwan Normal University, Taipei, Taiwan
Shih-Han Peng School of Life Science, Undergraduate and Graduate Programs of Nutrition Science, National Taiwan Normal University, Taipei, Taiwan
Chia-Hsin Chang School of Life Science, Undergraduate and Graduate Programs of Nutrition Science, National Taiwan Normal University, Taipei, Taiwan

DOI: https://doi.org/10.29219/fnr.v67.8991

Keywords: aromatase, breast cancer, lunasin, inflammation, estrogen receptor

Abstract

Background: Breast cancer is one of the most prevalent cancers in women. Its pathology comprises tumor cells and nearby stromal cells, accompanied by cytokines and stimulated molecules, resulting in a favorable microenvironment for tumor progression. Lunasin is a seed peptide with multiple bioactivities derived from seeds. However, the chemopreventive effect of lunasin on different characteristics of breast cancer has not been fully explored.

Objective: This study aims to explore the chemopreventive mechanisms of lunasin through inflammatory mediators and estrogen-related molecules in breast cancer cells.

Design: Estrogen-dependent MCF-7 and independent MDA-MB-231 breast cancer cells were used. The β-estradiol was used to mimic physiological estrogen. The gene expression, mediator secretion, cell vitality, and apoptosis impacting breast malignancy were explored.

Results: Lunasin did not affect normal MCF-10A cell growth but inhibited breast cancer cell growth, increased interleukin (IL)-6 gene expression and protein production at 24 h, and decreased its secretion at 48 h. In both breast cancer cells, aromatase gene and activity and estrogen receptor (ER)α gene expression were decreased by lunasin treatment, while ERβ gene levels were significantly increased in MDA-MB-231 cells. Moreover, lunasin decreased vascular endothelial growth factor (VEGF) secretion and cell vitality and induced cell apoptosis in both breast cancer cell lines. However, lunasin only decreased leptin receptor (Ob-R) mRNA expression in MCF-7 cells. Additionally, β-estradiol increased MCF-7-cell proliferation but not the proliferation of other cells; in particular, lunasin still inhibited MCF-7-cell growth and cell vitality in the presence of β-estradiol.

Conclusion: Seed peptide lunasin inhibited breast cancer cell growth by regulating inflammatory, angiogenic, and estrogen-related molecules, suggesting that lunasin is a promising chemopreventive agent.

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References

1.
World Health Organization. Breast cancer. 2021. Available from: https://www.who.int/news-room/fact-sheets/detail/breast-cancer [cited 4 May 2021].

2.
Velaei K, Samadi N, Barazvan B, Rad JS. Tumor microenvironment-mediated chemoresistance in breast cancer. Breast 2016; 30: 92–100. doi: 10.1016/j.breast.2016.09.002

3.
King J, Mir H, Singh S. Association of cytokines and chemokines in pathogenesis of breast cancer. Prog Mol Biol Transl Sci 2017; 151: 113–36. doi: 10.1016/bs.pmbts.2017.07.003

4.
Chan HJ, Petrossian K, Chen S. Structural and functional characterization of aromatase, estrogen receptor, and their genes in endocrine-responsive and -resistant breast cancer cells. J Steroid Biochem Mol Biol 2016; 161: 73–83. doi: 10.1016/j.jsbmb.2015.07.018

5.
Deshmukh SK, Srivastava SK, Poosarla T, Dyess DL, Holliday NP, Singh AP, et al. Inflammation, immunosuppressive microenvironment and breast cancer: opportunities for cancer prevention and therapy. Ann Transl Med 2019; 7: 593. doi: 10.21037/atm.2019.09.68

6.
Bulun SE, Lin Z, Imir G, Amin S, Demura M, Yilmaz B, et al. Regulation of aromatase expression in estrogen-responsive breast and uterine disease: from bench to treatment. Pharmacol Rev 2005; 57: 359–83. doi: 10.1124/pr.57.3.6

7.
Hsieh CC, Lin BF. Dietary factors regulate cytokines in murine models of systemic lupus erythematosus. Autoimmun Rev 2011; 11: 22–7. doi: 10.1016/j.autrev.2011.06.009

8.
De Cicco P, Catani MV, Gasperi V, Sibilano M, Quaglietta M, Savini I. Nutrition and breast cancer: a literature review on prevention, treatment and recurrence. Nutrients 2019; 11: 1514. doi: 10.3390/nu11071514

9.
Hsieh CC, Martínez-Villaluenga C, de Lumen BO, Hernández-Ledesma B. Updating the research on the chemopreventive and therapeutic role of the peptide lunasin. J Sci Food Agric 2018; 98: 2070–9. doi: 10.1002/jsfa.8719

10.
Hsieh CC, Hernández-Ledesma B, Jeong HJ, Park JH, de Lumen BO. Complementary roles in cancer prevention: protease inhibitor makes the cancer preventive peptide lunasin bioavailable. PLoS One 2010; 5: e8890. doi: 10.1371/journal.pone.0008890

11.
Fernández-Tomé S, Sanchón J, Recio I, Hernández-Ledesma B. Transepithelial transport of lunasin and derived peptides: inhibitory effects on the gastrointestinal cancer cells viability. J Food Compost Anal 2018; 68: 101–10. doi: 10.1016/j.jfca.2017.01.011

12.
Hsieh CC, Hernández-Ledesma B, de Lumen BO. Lunasin, a novel seed peptide, sensitizes human breast cancer MDA-MB-231 cells to aspirin-arrested cell cycle and induced apoptosis. Chem Biol Interact 2010; 186: 127–34. doi: 10.1016/j.cbi.2010.04.027

13.
Hernández-Ledesma B, Hsieh CC, de Lumen BO. Relationship between lunasin’s sequence and its inhibitory activity of histones H3 and H4 acetylation. Mol Nutr Food Res 2011; 55: 989–98. doi: 10.1002/mnfr.201000632

14.
Hsieh CC, Wang CH, Huang YS. Lunasin attenuates obesity associated metastasis of 4T1 breast cancer cell through anti-inflammatory property. Int J Mol Sci 2016; 17: 2109. doi: 10.3390/ijms17122109

15.
Hernández-Ledesma B, Hsieh CC, de Lumen BO. Anti-inflammatory and antioxidant properties of peptide lunasin in RAW 264.7 macrophages. Biochem Biophys Res Commun 2009; 390: 803–8. doi: 10.1016/j.bbrc.2009.10.053

16.
Hsieh CC, Chou MJ, Wang CH. Lunasin attenuates obesity-related inflammation in RAW264.7 cells and 3T3-L1 adipocytes by inhibiting inflammatory cytokine production. PLoS One 2017; 12: e0171969. doi: 10.1371/journal.pone.0171969

17.
Bhardwaj P, Au CC, Benito-Martin A, Ladumor H, Oshchepkova S, Moges R, et al. Estrogens and breast cancer: mechanisms involved in obesity-related development, growth and progression. J Steroid Biochem Mol Biol 2019; 189: 161–70. doi: 10.1016/j.jsbmb.2019.03.002

18.
Coppola S, Ghibelli L. GSH extrusion and the mitochondrial pathway of apoptotic signaling. Biochem Soc Trans 2000; 28: 56–61. doi: 10.1042/bst0280056

19.
Kawaguchi K, Sakurai M, Yamamoto Y, Suzuki E, Tsuda M, Kataoka TR, et al. Alteration of specific cytokine expression patterns in patients with breast cancer. Sci Rep 2019; 9: 2924. doi: 10.1038/s41598-019-39476-9

20.
Taher MY, Davies DM, Maher J. The role of the interleukin (IL)-6/IL-6 receptor axis in cancer. Biochem Soc Trans 2018; 46: 1449–62. doi: 10.1042/BST20180136

21.
Shen WH, Zhou JH, Broussard SR, Freund GG, Dantzer R, Kelley KW. Proinflammatory cytokines block growth of breast cancer cells by impairing signals from a growth factor receptor. Cancer Res 2002; 62: 4746–56.

22.
Lundin JI, Checkoway H. Endotoxin and cancer. Environ Health Perspect 2009; 117: 1344–50. doi: 10.1289/ehp.0800439

23.
Hsieh CC, Wang CH. Aspirin disrupts the crosstalk of angiogenic and inflammatory cytokines between 4T1 breast cancer cells and macrophages. Mediat Inflamm 2018; 2018: 6380643. doi: 10.1155/2018/6380643

24.
Jones SA, Jenkins BJ. Recent insights into targeting the IL-6 cytokine family in inflammatory diseases and cancer. Nat Rev Immunol 2018; 18: 773–89. doi: 10.1038/s41577-018-0066-7

25.
Lee HH, Jung J, Moon A, Kang H, Cho H. Antitumor and anti-invasive effect of apigenin on human breast carcinoma through suppression of IL-6 expression. Int J Mol Sci 2019; 20: 3143. doi: 10.3390/ijms20133143

26.
Masjedi A, Hashemi V, Hojjat-Farsangi M, Ghalamfarsa G, Azizi G, Yousefi M, et al. The significant role of interleukin-6 and its signaling pathway in the immunopathogenesis and treatment of breast cancer. Biomed Pharmacother 2018; 108: 1415–24. doi: 10.1016/j.biopha.2018.09.177

27.
Won HS, Kim YA, Lee JS, Jeon EK, An HJ, Sun DS, et al. Soluble interleukin-6 receptor is a prognostic marker for relapse-free survival in estrogen receptor-positive breast cancer. Cancer Invest 2013; 31: 516–21. doi: 10.3109/07357907.2013.826239

28.
Finetti F, Travelli C, Ercoli J, Colombo G, Buoso E, Trabalzini L. Prostaglandin E2 and cancer: insight into tumor progression and immunity. Biology (Basel) 2020; 9: 434. doi: 10.3390/biology9120434

29.
Harris RE, Casto BC, Harris ZM. Cyclooxygenase-2 and the inflammogenesis of breast cancer. World J Clin Oncol 2014; 5: 677–92. doi: 10.5306/wjco.v5.i4.677

30.
Hsieh CC, Chiu HH, Wang CH, Kuo CH. Aspirin modifies inflammatory mediators and metabolomic profiles and contributes to the suppression of obesity-associated breast cancer cell growth. Int J Mol Sci 2020; 21: 4652. doi: 10.3390/ijms21134652

31.
Sánchez-Jiménez F, Pérez-Pérez A, de la Cruz-Merino L, Sánchez-Margalet V. Obesity and breast cancer: role of leptin. Front Oncol 2019; 9: 596. doi: 10.3389/fonc.2019.00596

32.
Linares RL, Benítez JGS, Reynoso MO, Romero CG, Sandoval-Cabrera A. Modulation of the leptin receptors expression in breast cancer cell lines exposed to leptin and tamoxifen. Sci Rep 2019; 9(1): 19189. doi: 10.1038/s41598-019-55674-x

33.
Raut PK, Kim SH, Choi DY, Jeong GS, Park PH. Growth of breast cancer cells by leptin is mediated via activation of the inflammasome: critical roles of estrogen receptor signaling and reactive oxygen species production. Biochem Pharmacol 2019; 161: 73–88. doi: 10.1016/j.bcp.2019.01.006

34.
Gupta GK, Collier AL, Lee D, Hoefer RA, Zheleva V, van Reesema LLS, et al. Perspectives on triple-negative breast cancer: current treatment strategies, unmet needs, and potential targets for future therapies. Cancers (Basel) 2020; 12: 2392. doi: 10.3390/cancers12092392

35.
Madu CO, Wang S, Madu CO, Lu Y. Angiogenesis in breast cancer progression, diagnosis, and treatment. J Cancer 2020; 11: 4474–94. doi: 10.7150/jca.44313

36.
Hsieh CC, Huang YS. Aspirin breaks the cross-talk between 3T3-L1 adipocytes and 4T1 breast cancer cells by regulating cytokines production. PLoS One 2016; 11: e0147161. doi: 10.1371/journal.pone.0147161

37.
Acar Çevik U, Kaya Çavuşoğlu B, Sağlık BN, Osmaniye D, Levent S, Ilgın S, et al. Synthesis, docking studies and biological activity of new benzimidazole- triazolothiadiazine derivatives as aromatase inhibitor. Molecules 2020; 25: 1642. doi: 10.3390/molecules25071642

38.
Reyes-Vázquez L, Hernández AJA, Calderón-Aranda ES. Role of aromatase activation on sodium arsenite-induced proliferation, migration, and invasion of MDA-MB-231 and MDA-MB-453 breast cancer cell lines. Toxicology 2020; 437: 152440. doi: 10.1016/j.tox.2020.152440

39.
JavanMoghadam S, Weihua Z, Hunt KK, Keyomarsi K. Estrogen receptor alpha is cell cycle-regulated and regulates the cell cycle in a ligand-dependent fashion. Cell Cycle 2016; 15: 1579–90. doi: 10.1080/15384101.2016.1166327

40.
Hevir N, Trošt N, Debeljak N, Rižner TL. Expression of estrogen and progesterone receptors and estrogen metabolizing enzymes in different breast cancer cell lines. Chem Biol Interact 2011; 191: 206–16. doi: 10.1080/15384101.2016.1166327

41.
Schüler-Toprak S, Häring JE, Inwald C, Moehle C, Ortmann O, Treeck O. Agonists and knockdown of estrogen receptor beta differentially affect invasion of triple-negative breast cancer cells in vitro. BMC Cancer 2016; 16: 951. doi: 10.1186/s12885-016-2973-y

42.
Hernández-Ledesma B, Hsieh CC. Chemopreventive role of food-derived proteins and peptides: a review. Crit Rev Food Sci Nutr 2017; 57: 2358–76. doi: 10.1080/10408398.2015.1057632

43.
Jiang Q, Pan Y, Cheng Y, Li H, Liu D, Li H. Lunasin suppresses the migration and invasion of breast cancer cells by inhibiting matrix metalloproteinases-2/-9 via the FAK/Akt/ERK and NF-κB signaling pathways. Oncol Rep 2016; 36: 253–62. doi: 10.3892/or.2016.4798