Vol 59, No 4 (2021)
Original paper
Published online: 2021-12-09

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Soyasaponin Ag inhibits triple-negative breast cancer progression via targeting the DUSP6/MAPK signaling

Shoucheng Huang1, Ping Huang2, Huazhang Wu3, Song Wang1, Guodong Liu1
Pubmed: 34970732
Folia Histochem Cytobiol 2021;59(4):291-301.

Abstract

Introduction. Soyasaponins are triterpenoid glycosides discovered in soybean and have anti-cancer properties. Soyasaponin A was reported to repress estrogen-insensitive breast cancer cell proliferation. This study intends to explore the role of one isomer of soyasaponin A, i.e. soyasaponin Ag (Ssa Ag), in triple-negative breast cancer (TNBC) development.

Material and methods. Bioinformatic databases were used to predict DUSP6 expression in breast cancer (BC) as well as the correlation between the expression of DUSP6 (or MAPK1, MAPK14) with the prognosis of patients with BC. The expression of DUSP6/MAPK signaling-related genes (DUSP6, MAPK1, and MAPK14) in TNBC cell lines was assessed via Western blot analysis and RT-qPCR. Levels of cell apoptosis proteins (Bax and Bcl-2) in TNBC cells were assessed via Western blot analysis. CCK-8 assay, colony formation assay, and flow cytometry analysis were conducted for the measurement of TNBC cell growth and apoptosis. In vivo xenograft assay was employed for investigating the biological influence of Ssa Ag on tumor growth.

Results. The poor prognosis of BC patients was linked to the aberrant expression of DUSP6/MAPK pathway
genes. Low expression of DUSP6 or high expression of MAPK1 (or MAPK14) was correlated to poor prognosis. DUSP6 was downregulated while MAPK1 and MAPK14 were upregulated in TNBC cells versus normal cells. Ssa Ag upregulated DUSP6 expression while downregulated MAPK1 and MAPK14 expression, inhibiting the MAPK signaling pathway. Additionally, Ssa Ag promoted in vitro TNBC cell apoptosis and restrained cell growth, and repressed in vivo tumor growth.

Conclusions. Ssa Ag inhibited TNBC progression via upregulating DUSP6 and inactivating the MAPK signaling pathway.

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References

  1. Fahad Ullah M. Breast Cancer: Current Perspectives on the Disease Status. Adv Exp Med Biol. 2019; 1152: 51–64.
  2. Ghoncheh M, Pournamdar Z, Salehiniya H. Incidence and Mortality and Epidemiology of Breast Cancer in the World. Asian Pac J Cancer Prev. 2016; 17(S3): 43–46.
  3. Kolak A, Kamińska M, Sygit K, et al. Primary and secondary prevention of breast cancer. Ann Agric Environ Med. 2017; 24(4): 549–553.
  4. Carey LA, Dees EC, Sawyer L, et al. The triple negative paradox: primary tumor chemosensitivity of breast cancer subtypes. Clin Cancer Res. 2007; 13(8): 2329–2334.
  5. Sheng X, Dai H, Du Y, et al. LncRNA CARMN overexpression promotes prognosis and chemosensitivity of triple negative breast cancer via acting as miR143-3p host gene and inhibiting DNA replication. J Exp Clin Cancer Res. 2021; 40(1): 205.
  6. Boyle P. Triple-negative breast cancer: epidemiological considerations and recommendations. Ann Oncol. 2012; 23 Suppl 6: vi7–v12.
  7. Stevens KN, Vachon CM, Couch FJ. Genetic susceptibility to triple-negative breast cancer. Cancer Res. 2013; 73(7): 2025–2030.
  8. De Cicco P, Catani MV, Gasperi V, et al. Nutrition and Breast Cancer: A Literature Review on Prevention, Treatment and Recurrence. Nutrients. 2019; 11(7).
  9. Liyanage PY, Hettiarachchi SD, Zhou Y, et al. Nanoparticle-mediated targeted drug delivery for breast cancer treatment. Biochim Biophys Acta Rev Cancer. 2019; 1871(2): 419–433.
  10. Yang SH, Tsatsakis AM, Tzanakakis G, et al. Soyasaponin Ag inhibits α‑MSH‑induced melanogenesis in B16F10 melanoma cells via the downregulation of TRP‑2. Int J Mol Med. 2017; 40(3): 631–636.
  11. Kamo S, Suzuki S, Sato T. The content of soyasaponin and soyasapogenol in soy foods and their estimated intake in the Japanese. Food Sci Nutr. 2014; 2(3): 289–297.
  12. Tsai WT, Nakamura Y, Akasaka T, et al. Soyasaponin ameliorates obesity and reduces hepatic triacylglycerol accumulation by suppressing lipogenesis in high-fat diet-fed mice. J Food Sci. 2021; 86(5): 2103–2117.
  13. Shiraiwa M, Harada K, Okubo K. Composition and structure of "group B saponin" in soybean seed. Agric Biol Chem. 1991; 55(4): 911–917.
  14. Guang C, Chen J, Sang S, et al. Biological functionality of soyasaponins and soyasapogenols. J Agric Food Chem. 2014; 62(33): 8247–8255.
  15. Xiao JX, Huang GQ, Zhang SH. Soyasaponins inhibit the proliferation of Hela cells by inducing apoptosis. Exp Toxicol Pathol. 2007; 59(1): 35–42.
  16. Yang SH, Ahn EK, Lee JA, et al. Soyasaponins Aa and Ab exert an anti-obesity effect in 3T3-L1 adipocytes through downregulation of PPARγ. Phytother Res. 2015; 29(2): 281–287.
  17. Zhang W, Popovich DG. Chemical and biological characterization of oleanane triterpenoids from soy. Molecules. 2009; 14(8): 2959–2975.
  18. Hsu CC, Lin TW, Chang WW, et al. Soyasaponin-I-modified invasive behavior of cancer by changing cell surface sialic acids. Gynecol Oncol. 2005; 96(2): 415–422.
  19. Omar A, Kalra RS, Putri J, et al. Soyasapogenol-A targets CARF and results in suppression of tumor growth and metastasis in p53 compromised cancer cells. Sci Rep. 2020; 10(1): 6323.
  20. Guo YJ, Pan WW, Liu SB, et al. ERK/MAPK signalling pathway and tumorigenesis. Exp Ther Med. 2020; 19(3): 1997–2007.
  21. Fang JY, Richardson BC. The MAPK signalling pathways and colorectal cancer. Lancet Oncol. 2005; 6(5): 322–327.
  22. Sun QY, Ding LW, Johnson K, et al. SOX7 regulates MAPK/ERK-BIM mediated apoptosis in cancer cells. Oncogene. 2019; 38(34): 6196–6210.
  23. Chen L, Wang Y, Luan H, et al. DUSP6 protects murine podocytes from high glucose‑induced inflammation and apoptosis. Mol Med Rep. 2020; 22(3): 2273–2282.
  24. Missinato MA, Saydmohammed M, Zuppo DA, et al. Dusp6 attenuates Ras/MAPK signaling to limit zebrafish heart regeneration. Development. 2018; 145(5).
  25. Relav L, Estienne A, Price CA. Dual-specificity phosphatase 6 (DUSP6) mRNA and protein abundance is regulated by fibroblast growth factor 2 in sheep granulosa cells and inhibits c-Jun N-terminal kinase (MAPK8) phosphorylation. Mol Cell Endocrinol. 2021; 531: 111297.
  26. Wu F, McCuaig RD, Sutton CR, et al. Nuclear-Biased DUSP6 Expression is Associated with Cancer Spreading Including Brain Metastasis in Triple-Negative Breast Cancer. Int J Mol Sci. 2019; 20(12).
  27. Muda M, Boschert U, Dickinson R, et al. MKP-3, a novel cytosolic protein-tyrosine phosphatase that exemplifies a new class of mitogen-activated protein kinase phosphatase. J Biol Chem. 1996; 271(8): 4319–4326.
  28. Fan MJ, Liang SM, He PJ, et al. Dusp6 inhibits epithelial-mesenchymal transition in endometrial adenocarcinoma via ERK signaling pathway. Radiol Oncol. 2019; 53(3): 307–315.
  29. Hsu WC, Chen MY, Hsu SC, et al. DUSP6 mediates T cell receptor-engaged glycolysis and restrains T cell differentiation. Proc Natl Acad Sci U S A. 2018; 115(34): E8027–E8036.
  30. James NE, Beffa L, Oliver MT, et al. Inhibition of DUSP6 sensitizes ovarian cancer cells to chemotherapeutic agents via regulation of ERK signaling response genes. Oncotarget. 2019; 10(36): 3315–3327.
  31. Ma R, Ma L, Weng W, et al. DUSP6 SUMOylation protects cells from oxidative damage via direct regulation of Drp1 dephosphorylation. Sci Adv. 2020; 6(13): eaaz0361.
  32. Vo AH, Swaggart KA, Woo A, et al. Dusp6 is a genetic modifier of growth through enhanced ERK activity. Hum Mol Genet. 2019; 28(2): 279–289.
  33. Yang SH, Le B, Androutsopoulos VP, et al. Anti-inflammatory effects of soyasapogenol I-αa via downregulation of the MAPK signaling pathway in LPS-induced RAW 264.7 macrophages. Food Chem Toxicol. 2018; 113: 211–217.
  34. Anbalagan M, Ali A, Jones RK, et al. Peptidomimetic Src/pretubulin inhibitor KX-01 alone and in combination with paclitaxel suppresses growth, metastasis in human ER/PR/HER2-negative tumor xenografts. Mol Cancer Ther. 2012; 11(9): 1936–1947.
  35. Luby AO, Subramanian C, Buchman LK, et al. Amifostine Prophylaxis in Irradiated Breast Reconstruction: A Study of Oncologic Safety In Vitro. Ann Plast Surg. 2020; 85(4): 424–429.
  36. Wiggins AKA, Kharotia S, Mason JK, et al. α-Linolenic Acid Reduces Growth of Both Triple Negative and Luminal Breast Cancer Cells in High and Low Estrogen Environments. Nutr Cancer. 2015; 67(6): 1001–1009.
  37. Yang SH, Tsatsakis AM, Tzanakakis G, et al. Soyasaponin Ag inhibits α‑MSH‑induced melanogenesis in B16F10 melanoma cells via the downregulation of TRP‑2. Int J Mol Med. 2017; 40(3): 631–636.
  38. Omar A, Kalra RS, Putri J, et al. Soyasapogenol-A targets CARF and results in suppression of tumor growth and metastasis in p53 compromised cancer cells. Sci Rep. 2020; 10(1): 6323.
  39. Góral I, Wojciechowski K. Surface activity and foaming properties of saponin-rich plants extracts. Adv Colloid Interface Sci. 2020; 279: 102145.
  40. Güçlü-Ustündağ O, Mazza G. Saponins: properties, applications and processing. Crit Rev Food Sci Nutr. 2007; 47(3): 231–258.
  41. Ellington AA, Berhow M, Singletary KW. Induction of macroautophagy in human colon cancer cells by soybean B-group triterpenoid saponins. Carcinogenesis. 2005; 26(1): 159–167.
  42. Ellington AA, Berhow MA, Singletary KW. Inhibition of Akt signaling and enhanced ERK1/2 activity are involved in induction of macroautophagy by triterpenoid B-group soyasaponins in colon cancer cells. Carcinogenesis. 2006; 27(2): 298–306.
  43. Hsu CC, Lin TW, Chang WW, et al. Soyasaponin-I-modified invasive behavior of cancer by changing cell surface sialic acids. Gynecol Oncol. 2005; 96(2): 415–422.
  44. Lee IA, Park YJ, Joh EH, et al. Soyasaponin Ab ameliorates colitis by inhibiting the binding of lipopolysaccharide (LPS) to Toll-like receptor (TLR)4 on macrophages. J Agric Food Chem. 2011; 59(24): 13165–13172.
  45. Pei Y, Zhao H, Du X, et al. [Apoptosis effects on human esophageal cancer cells by soyasaponin Bb and its machanism]. Wei Sheng Yan Jiu. 2010; 39(4): 444–446.
  46. Bermudez O, Pagès G, Gimond C. The dual-specificity MAP kinase phosphatases: critical roles in development and cancer. Am J Physiol Cell Physiol. 2010; 299(2): C189–C202.
  47. Hu X, Tang Z, Ma S, et al. Tripartite motif-containing protein 7 regulates hepatocellular carcinoma cell proliferation via the DUSP6/p38 pathway. Biochem Biophys Res Commun. 2019; 511(4): 889–895.
  48. Keyse SM. Dual-specificity MAP kinase phosphatases (MKPs) and cancer. Cancer Metastasis Rev. 2008; 27(2): 253–261.
  49. Zhang Q, Fan XY, Guo WL, et al. The protective mechanisms of macroalgae Laminaria japonica consumption against lipid metabolism disorders in high-fat diet-induced hyperlipidemic rats. Food Funct. 2020; 11(4): 3256–3270.
  50. Ramkissoon A, Chaney KE, Milewski D, et al. Targeted Inhibition of the Dual Specificity Phosphatases DUSP1 and DUSP6 Suppress MPNST Growth via JNK. Clin Cancer Res. 2019; 25(13): 4117–4127.
  51. Song H, Wu C, Wei C, et al. Silencing of DUSP6 gene by RNAi-mediation inhibits proliferation and growth in MDA-MB-231 breast cancer cells: an in vitro study. Int J Clin Exp Med 2015. 8(7): p. : 10481–90.
  52. Wu X, Chen S, Lu C. Amyloid precursor protein promotes the migration and invasion of breast cancer cells by regulating the MAPK signaling pathway. Int J Mol Med. 2020; 45(1): 162–174.
  53. Park S, Han SH, Kim HG, et al. PRPF4 is a novel therapeutic target for the treatment of breast cancer by influencing growth, migration, invasion, and apoptosis of breast cancer cells via p38 MAPK signaling pathway. Mol Cell Probes. 2019; 47: 101440.
  54. Nokin MJ, Bellier J, Durieux F, et al. Methylglyoxal, a glycolysis metabolite, triggers metastasis through MEK/ERK/SMAD1 pathway activation in breast cancer. Breast Cancer Res. 2019; 21(1): 11.
  55. Yang SH, Le B, Androutsopoulos VP, et al. Anti-inflammatory effects of soyasapogenol I-αa via downregulation of the MAPK signaling pathway in LPS-induced RAW 264.7 macrophages. Food Chem Toxicol. 2018; 113: 211–217.