Response of beta-cateninand baxgene expression in liver tissue of mice with melanoma cancer to a course of aerobic exercise with consumption of nettle extract
Subject Areas : Experimental physiology and pathologyjavid esmaeelpour 1 , alireza barari 2 , Ahmad Abdi 3 , Hossein Abednatanzi 4
1 - Department of Sport Physiology, Ayatollah Amoli Branch, Islamic Azad University, Amol, Iran
2 - Department of sport physiology, Ayatollah amoli branch, Islamic Azad University, amol, Iran.
3 - Department of Exercise Physiology, Ayatollah Amoli Branch, Islamic Azad University, Amol, Iran
4 - Department of Physical Education & Sports Science, Islamic Azad University, research &Science Branch, Tehran, Iran
Keywords: Nettle extract, Apoptosis, WNT/beta-catenin pathway, Melanoma cancer,
Abstract :
Background & Aim: The aim of this study was to investigate the response of beta-cateninand bax gene expression in liver tissue of mice with melanoma to a period of aerobic exercise with nettle extract.
Materials and methods: In this study, 20 adult male rats were randomly divided into 4 groups including: control, exercise, extract and exercise + extract. The training program consisted of 30 minutes of running on a treadmill without a slope at a speed of 16 meters per minute for the first week, and one meter per minute was added every week until it reached 22 meters per minute in the eighth week. One week after melanoma induction, the experimental group consumed 30 mg / kg / day of nettle ethanolic extract orally for 8 weeks. RT PCR was used to measure the expression of beta-cateninand baxgenes.
Results: Data analysis showed that Beta-catenin gene expression was increased in the experimental groups compared to the control group; But did not reach a significant level (p = 0.103). The results also showed that BAX gene expression was significantly reduced in the experimental groups compared to the control group (p = 0.026).
Conclusion: The results show that consumption of nettle extract along with aerobic exercise by reducing BAX levels and increasing beta-catenin in activating the WNT / beta-catenin signal pathway and apoptosis has an immune stimulus to prevent tumor growth and cancer progression.
1. Wang B, Tian T, Kalland KH, Ke X, Qu Y. Targeting Wnt/β-catenin signaling for cancer immunotherapy. Trends in pharmacological sciences. 2018 Jul 1;39(7):648-58.
2. Galluzzi L, Spranger S, Fuchs E, López-Soto A. WNT Signaling in Cancer Immunosurveillance. Trends Cell Biol. 2019;29:44–65. doi: 10.1016/j.tcb.2018.08.005.
3. Scholz SL, Cosgarea I, Süßkind D, Murali R, Möller I, Reis H, et al. NF1 mutations in conjunctival melanoma. Br J Cancer. 2018 May;118(9):1243–7.
4. Dissanayake SK, Wade M, Johnson CE, O’Connell MP, Leotlela PD, French AD, et al. The Wnt5A/protein kinase C pathway mediates motility in melanoma cells via the inhibition of metastasis suppressors and initiation of an epithelial to mesenchymal transition. J Biol Chem. 2007 Jun;282(23):17259–71.
5. Roel Nusse H.C. Wnt/b-catenin signaling, disease, and emerging therapeutic modalities. Cell. 2017;169:985–999. doi: 10.1016/j.cell.2017.05.016.
6. Alok A, Lei Z, Jagannathan NS, Kaur S, Harmston N, Rozen SG, Tucker-Kellogg L, Virshup DM. Wnt proteins synergize to activate β-catenin signaling. Journal of cell science. 2017 May 1;130(9):1532-44.
7. De A. Wnt/ca2+ signaling pathway: A brief overview. Acta Biochim. Biophys. Sin. 2011;43:745–756.
8. Stolz A, Neufeld K, Ertych N, Bastians H. Wnt-mediated protein
stabilization ensures proper mitotic microtubule assembly and chromosome segregation. EMBO Rep. 2015;16:490–499. doi: 10.15252/embr.201439410.
9. O’Connell MP, Weeraratna AT. Hear the Wnt Ror: how melanoma cells adjust to changes in Wnt. Pigment Cell Melanoma Res. 2009 Dec;22(6):724–39.
10. Delmas V, Beermann F, Martinozzi S, Carreira S, Ackermann J, Kumasaka M, et al. Beta-catenin induces immortalization of melanocytes by suppressing p16INK4a expression and cooperates with N-Ras in melanoma development. Genes Dev. 2007 Nov;21(22):2923–35.
11. Anastas J.N, Moon R.T. WNT signalling pathways as therapeutic targets in cancer. Nat. Rev. Cancer. 2013;13:11–26. doi: 10.1038/nrc3419.
12. Chen EY, DeRan MT, Ignatius MS, Grandinetti KB, Clagg R, McCarthy KM, Lobbardi RM, Brockmann J, Keller C, Wu X. Glycogen synthase kinase 3 inhibitors induce the canonical WNT/β-catenin pathway to suppress growth and self-renewal in embryonal rhabdomyosarcoma. Proc. Natl. Acad. Sci. USA. 2014;111:5349–5354.
13. Pacheco-Pinedo E.C, Durham AC, Stewart K M, Goss AM, Lu MM, Demayo FJ, Morrisey EE. Wnt/β-catenin signaling accelerates mouse lung tumorigenesis by imposing an embryonic distal progenitor phenotype on lung epithelium. J. Clin. Investig. 2011;121:1935–1945.
14. Fulda S, Debatin K. Extrinsic versus intrinsic apoptosis pathways in anticancer chemotherapy. Oncogene. 2006;25:4798–4811.
15. Trisciuoglio D, Del Bufalo D. New insights into the roles of antiapoptotic members of the Bcl-2 family in melanoma progression and therapy. Drug Discov Today. 2021;S1359- 6446(21)00059-3.
16. Rubio C., Mendoza C., Trejo C., Custodio V, Rubio-Osornio M, Hernández L, González E, Paz C. Activation of the Extrinsic and Intrinsic Apoptotic Pathways in Cerebellum of Kindled Rats. Cerebellum. 2019;18:750–760.
17. Gogvadze V, Orrenius S, Zhivotovsky B. Multiple pathways of cytochrome c release from mitochondria in apoptosis. Biochim Biophys Acta Bioenergy. 2006;1757:639–647.
18. Karikas G. Anticancer and chemopreventing natural products: some biochemical and therapeutic aspects. J BUON. 2010;15:627–638.
19. Joshi, BC, Mukhija, M, Kalia, AN. Pharmacognostical review of Urtica dioica L. IJGP. 2014;8:201–209.
20. Durak, I, Biri, H, Devrim, E, Sözen, S, Avcı, A. Aqueous extract of Urtica dioica makes significant inhibition on adenosine deaminase activity in prostate tissue from patients with prostate cancer. Cancer Biol Ther. 2004;3:855–857.
21. Konrad, L, Müller, HH, Lenz, C, Laubinger, H, Aumüller, G, Lichius, JJ. Antiproliferative effect on human prostate cancer cells by a stinging nettle root (Urtica dioica) extract. Planta Med. 2000;66:44–47.
22. Akinyemiju T, Abera S, Ahmed M, Alam N, Alemayohu M.A, Allen C, Al-Raddadi, R, Alvis-Guzman N, Amoako Y, Artaman A, Ayele T.A, Barac A, Bensenor I, Berhane A, Bhutta Z, Castillo-Rivas J, Chitheer A, Choi J.Y,Cowie B .The Burden of Primary Liver Cancer and Underlying Etiologies (2017). JAMA oncology, 3(12), 1683–1691.
23. Kenfield S.A, Batista J.L, Jahn, J. L, Downer M. K, Van Blarigan E.L, Sesso H.D, Giovannucci E.L, Stampfer M.J and Chan J.M.(2015). Development and Application of a Lifestyle Score for Prevention of Lethal Prostate Cancer. Journal of the National Cancer Institute, 108(3),djv329.
24. Keimling M, Behrens G, Schmid D, Jochem C and Leitzmann M.F.(2014). The association between physical activity and bladder cancer: systematic review and meta-analysis. British journal of cancer, 110(7), 1862–1870.
25. Lei MJ, Dong Y, Sun CX and Zhang XH: Resveratrol inhibits proliferation, promotes differentiation and melanogenesis in HT-144 melanoma cells through inhibition of MEK/ERK kinase pathway. Microb Pathog 111: 410-413, 2017.
26. Kim TH, Chang JS, Park KS, Park J, Kim N, Lee JI and Kong I.D. (2017). Effects of exercise training on circulating levels of Dickkpof-1 and secreted frizzled-related protein-1 in breast cancer survivors: A pilot single-blind randomized controlled trial. PloS one, 12(2), e0171771.
27. Voorzanger-Rousselot N, Journe F, Doriath V, Body JJ, Garnero P. Assessment of circulating Dickkopf-1 with a new two-site immunoassay in healthy subjects and women with breast cancer and bone metastases. Calcif Tissue Int. 2009;84: 348–354.
28. apietto AH, Kim S, Sanford DE, Linehan DC, Hikida M, Kumosaki T, et al. Down-regulation of PLCgamma2-beta-catenin pathway promotes activation and expansion of myeloid-derived suppressor cells in cancer. J Exp Med. 2013;210: 2257–2271.
29. Yamabuki T, Takano A, Hayama S, Ishikawa N, Kato T, Miyamoto M, et al. Dikkopf-1 as a novel serologic and prognostic biomarker for lung and esophageal carcinomas. Cancer Res. 2007;67: 2517–2525
30. Liu Y, Tang W, Xie L, Wang J, Deng Y, Peng Q, et al. Prognostic significance of dickkopf-1 overexpression in solid tumors: a meta-analysis. Tumour Biol. 2014;35: 3145–3154. D'Amico L, Mahajan S, Capietto AH, Yang Z, Zamani A, Ricci B, et al.
31. Dickkopf-related protein 1 (Dkk1) regulates the accumulation and function of myeloid derived suppressor cells in cancer. J Exp Med. 2016;213: 827–840.
32. Kerschan-Schindl K, Thalmann MM, Weiss E, Tsironi M, Foger-Samwald U, Meinhart J, et al. Changes in serum levels of myokines and Wnt-antagonists after an ultramarathon race. PLoS One. 2015;10: e0132478 10.1371/journal.pone.0132478
33. Bayod S, Mennella I, Sanchez-Roige S, Lalanza JF, Escorihuela RM, Camins A, et al. Wnt pathway regulation by long-term moderate exercise in rat hippocampus. Brain Res. 2014;1543: 38–48.
34. Spillane M, Schwarz N, Willoughby DS. Upper-body resistance exercise augments vastus lateralis androgen receptor-DNA binding and canonical Wnt/beta-catenin signaling compared to lower-body resistance exercise in resistance-trained men without an acute increase in serum testosterone. Steroids. 2015;98: 63–71.
35. Staal FJ, Luis TC, Tiemessen MM. WNT signalling in the immune system: WNT is spreading its wings. Nat Rev Immunol. 2008;8: 581–593.
36. Gattinoni L, Ji Y, Restifo NP. Wnt/beta-catenin signaling in T-cell immunity and cancer immunotherapy. Clin Cancer Res. 2010;16: 4695–4701.
37. Cao Dinh H, Beyer I, Mets T, Onyema OO, Njemini R, Renmans W, De Waele M, Jochmans K, Vander Meeren S, Bautmans I. Effects of physical exercise on markers of cellular immunosenescence: a systematic review. Calcified tissue international. 2017 Feb;100:193-215.
38. Ramadan MA, Shawkey AE, Rabeh MA and Abdellatif AO. (2019). Expression of P53, BAX, and BCL-2 in human malignant melanoma and squamous cell carcinoma cells after tea tree oil treatment in vitro. Cytotechnology, 71(1), 461–473.
39. Colotta F, Allavena P, Sica A, Garlanda C, Mantovani A. Cancer-related inflammation, the seventh hallmark of cancer: links to genetic instability. Carcinogenesis. 2009;30:1073–1081.
40. Takahashi R, Markovic SN, Scrable HJ. Dominant effects of Δ40p53 on p53 function and melanoma cell fate. J Invest Dermatol. 2014;134:791–800.
41. Nylander K, Nilsson P, Mehle C, Roos G. p53 mutations, protein expression and cell proliferation in squamous cell carcinomas of the head and neck. Br J Cancer. 1995;71:826.
42. Hassan M, Watari H, AbuAlmaaty A, Ohba Y, Sakuragi N. Apoptosis and molecular targeting therapy in cancer. Biomed Res Int. 2014;2014:150845.
