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Quercetin modulates Wnt signaling components in prostate cancer cell line by inhibiting cell viability, migration, and metastases

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Tumor Biology

Abstract

Epithelial-mesenchymal transition (EMT) is a plastic transition in tumor progression during which cancer cells undergo dramatic changes acquiring highly invasive properties. Transforming growth factor-β (TGF-β) is an inducer of EMT in epithelial cells and is obligatory for acquiring invasive phenotype in carcinoma. TGF-β plays a vital role in metastasis and tumorigenesis in prostate cancer, and mutations in the components of Wnt signaling pathways are associated with various kinds of cancers including prostate cancer. The purpose of this study was to identify alterations in Wnt signaling pathway components involved during prostate cancer progression and to determine the effect of quercetin on TGF-β-induced EMT in prostate cancer (PC-3) cell line. The expression of epithelial and mesenchymal markers and the components of Wnt signaling pathway were evaluated by real-time polymerase chain reaction. It was observed that quercetin prevented TGF-β-induced expression of vimentin and N-cadherin and increased the expression of E-cadherin in PC-3 cells, thus preventing TGF-β-induced EMT. Furthermore, the relative expression of Twist, Snail, and Slug showed that quercetin significantly decreased TGF-β-induced expression of Twist, Snail, and Slug. In the present study, the expression of epithelial markers were found to be upregulated in naive state and downregulated in induced state whereas the mesenchymal markers were found to be downregulated in naive state and upregulated in induced state. Thus, our study concludes that quercetin may prevent prostate cancer metastasis by regulating the components of Wnt pathway.

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References

  1. Siegel R, Miller K, Jemal A. Cancer statistics, 2015. CA Cancer J Clin 2015;65(1):29.

  2. Yang J, Weinberg RA. Epithelial-mesenchymal transition: at the crossroads of development and tumor metastasis. Dev Cell. 2008;14(6):818–29.

    Article  CAS  PubMed  Google Scholar 

  3. Grant CM, Kyprianou N. Epithelial mesenchymal transition (EMT) in prostate growth and tumor progression. Transl Androl Urol. 2013;2(4):202–11.

    PubMed  PubMed Central  Google Scholar 

  4. Thiery JP, Acloque H, Huang RYJ, Nieto MA. Epithelial-mesenchymal transitions in development and disease. Cell. 2009;139(5):871–90.

    Article  CAS  PubMed  Google Scholar 

  5. Moustakas A, Heldin P. Biochimica et Biophysica Acta TGF β and matrix-regulated epithelial to mesenchymal transition ☆. BBA - Gen Subj. 2014;1840(8):2621–2634.

  6. Muraoka RS, Dumont N, Ritter CA, Dugger TC, Brantley DM, Chen J, et al. Blockade of TGF-beta inhibits mammary tumor cell viability, migration, and metastases. J Clin Invest. 2002;109(12):1551–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Zavadil J, Böttinger EP. TGF-β and epithelial-to-mesenchymal transitions. Oncogene. 2005;24(37):5764–74.

    Article  CAS  PubMed  Google Scholar 

  8. Anastas JN, Moon RT. WNT signalling pathways as therapeutic targets in cancer. Nat Rev Cancer. Nature Publishing Group2012;13(1):11–26.

    Article  Google Scholar 

  9. Valkenburg KC, Graveel CR, Zylstra-Diegel CR, Zhong Z, Williams BO. Wnt/β-catenin signaling in normal and cancer stem cells. Cancers (Basel). 2011;3(2):2050–79.

    Article  CAS  Google Scholar 

  10. Baruah MM, Sharma N. Effect of flavonoid on reversal of TGF-β induced epithelial to mesenchymal transition in prostate cancer (PC-3) cell line. Ind J Clin Biochem. 2015;30(1):S83.

    Google Scholar 

  11. Chirumbolo S. The role of quercetin, flavonols and flavones in modulating inflammatory cell function. Inflamm Allergy Drug Targets. 2010;9(4):263–85.

    Article  CAS  PubMed  Google Scholar 

  12. Papiez MA, Cierniak A, Krzysciak W, Bzowska M, Taha HM, Jozkowicz A, et al. The changes of antioxidant defense system caused by quercetin administration do not lead to DNA damage and apoptosis in the spleen and bone marrow cells of rats. Food Chem Toxicol. 2008;46(9):3053–8.

    Article  CAS  PubMed  Google Scholar 

  13. Baruah MM, Sharma N, Khandwekar AP, Lavale G-, Author C. Flavonoids and Prostate Cancer. AIJRFANS. 2016;15(1):01–07.

  14. Kim GT, Lee SH, Kim II J, Kim YM. Quercetin regulates the sestrin 2-AMPK-p38 MAPK signaling pathway and induces apoptosis by increasing the generation of intracellular ROS in a p53-independent manner. Int J Mol Med. 2014;33(4):863–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Chan S-T, Yang N-C, Huang C-S, Liao J-W, Yeh S-L. Quercetin enhances the antitumor activity of trichostatin a through upregulation of p53 protein expression in vitro and in vivo. PLoS One 2013;8(1):e54255.

  16. Shan B-E, Wang M-X, Li R. Quercetin inhibit human SW480 colon cancer growth in association with inhibition of cyclin D1 and survivin expression through Wnt/beta-catenin signaling pathway. Cancer Investig. 2009;27(6):604–12.

    Article  CAS  Google Scholar 

  17. Pozarowski P, Darzynkiewicz Z. Analysis of cell cycle by flow cytometry. Methods Mol Biol. 2004;281:301–11.

    CAS  PubMed  Google Scholar 

  18. Schmittgen TD, Livak KJ. Analyzing real-time PCR data by the comparative CT method. Nat Protoc. 2008;3(6):1101–8.

    Article  CAS  PubMed  Google Scholar 

  19. BD Biosciences. Caspase-3 Activation: an indicator of apoptosis in image-based assays. BD Biosciences. 2012. https://www.bdbiosciences.com/documents/Bioimaging_AppNote_Apoptosis.pdf. Accessed 10 Nov 2015.

  20. Vermes I, Haanen C, Steffens-Nakken H, Reutelingsperger C. A novel assay for apoptosis. Flow cytometric detection of phosphatidylserine expression on early apoptotic cells using fluorescein labelled Annexin V. J Immunol Methods. 1995;184(1):39–51.

    Article  CAS  PubMed  Google Scholar 

  21. Radisky DC. Epithelial-mesenchymal transition. J Cell Sci. 2005;118(19):4325–6.

    Article  CAS  PubMed  Google Scholar 

  22. Nistico P, Bissell MJ, Radisky DC. Epithelial-mesenchymal transition: general principles and pathological relevance with special emphasis on the role of matrix metalloproteinases. Cold Spring Harb Perspect Biol. 2012;4(2):a011908.

    Article  PubMed  PubMed Central  Google Scholar 

  23. Ambrosini G, Adida C, Altieri DC. A novel anti-apoptosis gene, survivin, expressed in cancer and lymphoma. Nat Med. 1997;3(8):917–21.

    Article  CAS  PubMed  Google Scholar 

  24. Zhong H, Marzo AM De, Laughner E, Lim M, Hilton D A, Zagzag D, et al. Overexpression of hypoxia-inducible factor 1α in common human cancers and their metastases 1. New York. 2000;(22):5830–5.

  25. Son H, Moon A. Epithelial-mesenchymal transition and cell invasion. Toxicol Res. 2010;26(4):245–52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Moreno-Bueno G, Portillo F, Cano A. Transcriptional regulation of cell polarity in EMT and cancer. Oncogene. 2008;27:6958–69.

    Article  CAS  PubMed  Google Scholar 

  27. López-Nouoa JM, Nieto MA. Inflammation and EMT: an alliance towards organ fibrosis and cancer progression. EMBO Mol Med. 2009;1(6–7):303–14.

    Article  Google Scholar 

  28. Thuault S, Valcourt U, Petersen M, Manfioletti G, Heldin CH, Moustakas A. Transforming growth factor-β employs HMGA2 to elicit epithelial-mesenchymal transition. J Cell Biol. 2006;174(2):175–83.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Nawshad A, LaGamba D, Polad A, Hay ED. Transforming growth factor-β signaling during epithelial-mesenchymal transformation: implications for embryogenesis and tumor metastasis. Cells Tissues Organs. 2005;179(1–2):11–23.

    Article  CAS  PubMed  Google Scholar 

  30. Larue L, Bellacosa A. Epithelial-mesenchymal transition in development and cancer: role of phosphatidylinositol 3′ kinase/AKT pathways. Oncogene. 2005;24(50):7443–54.

    Article  CAS  PubMed  Google Scholar 

  31. Malage RD. Studies on regulation of TGF-β and markers of epithelial to mesenchymal transition in breast cancer cells. Dissertation, Jawaharlal Nehru University. 2008;110067.

  32. Chen D, Wilkinson CRM, Watt S, Penkett CJ, Toone WM, Jones N, et al. Multiple pathways differentially regulate global oxidative stress responses in fission yeast. Mol Biol Cell. 2008;19(1):308–17.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Moustakas A, Heldin C-HH. The regulation of TGFbeta signal transduction. Development. 2009;136(22):3699–714.

    Article  CAS  PubMed  Google Scholar 

  34. Lin YS, Tsai PH, Kandaswami CC, Cheng CH, Ke FC, Lee PP, et al. Effects of dietary flavonoids, luteolin, and quercetin on the reversal of epithelial-mesenchymal transition in A431 epidermal cancer cells. Cancer Sci. 2011;102(10):1829–39.

    Article  CAS  PubMed  Google Scholar 

  35. Deng XH, Song HY, Zhou YF, Yuan GY, Zheng FJ. Effects of quercetin on the proliferation of breast cancer cells and expression of survivin in vitro. Exp Ther Med. 2013;6(5):1155–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Salem-Alrawaiq N, Abdullah A. A review of flavonoid quercetin: metabolism, bioactivity and antioxidant properties. Int J PharmTech Res. 2014;6(3):933–41.

    Google Scholar 

  37. Uygur B, Wu W-S. SLUG promotes prostate cancer cell migration and invasion via CXCR4/CXCL12 axis. Mol Cancer BioMed Central Ltd; 2011;10(1):139.

  38. Zhang K, Chen D, Jiao X, Zhang S, Liu X, Cao J, et al. Slug enhances invasion ability of pancreatic cancer cells through upregulation of matrix metalloproteinase-9 and actin cytoskeleton remodeling. Lab Investig. Nature Publishing Group2011;91(3):426–38.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Kurrey NK, Amit K, Bapat SA. Snail and slug are major determinants of ovarian cancer invasiveness at the transcription level. Gynecol Oncol. 2005;97(1):155–65.

    Article  CAS  PubMed  Google Scholar 

  40. Yang J, Mani SA, Donaher JL, Ramaswamy S, Itzykson RA, Come C, et al. Twist, a master regulator of morphogenesis, plays an essential role in tumor metastasis Ben Gurion University of the Negev. Cell. 2004;117:927–39.

    Article  CAS  PubMed  Google Scholar 

  41. Bhat FA, Sharmila G, Balakrishnan S, Arunkumar R, Elumalai P, Suganya S, et al. Quercetin reverses EGF-induced epithelial to mesenchymal transition and invasiveness in prostate cancer (PC-3) cell line via EGFR/PI3K/Akt pathway. J Nutr Biochem. Elsevier Inc.2014;25(11):1132–9.

    Article  CAS  PubMed  Google Scholar 

  42. Kim H, Seo EM, Sharma AR, Ganbold B, Park J, Sharma G, et al. Regulation of Wnt signaling activity for growth suppression induced by quercetin in 4T1 murine mammary cancer cells. Int J Oncol. 2013;43(4):1319–25.

    CAS  PubMed  Google Scholar 

  43. Novo MCT, Osugui L, dos Reis VO, Longo-Maugeri IM, Mariano M, Popi AF. Blockage of Wnt/β-catenin signaling by quercetin reduces survival and proliferation of B-1 cells in vitro. Immunobiology Elsevier GmbH.; 2015;220(1):60–67.

  44. Maso V, Calgarotto AKA, Franchi GCA, Nowill AED, Filho PLA, Vassallo J, et al. Multitarget effects of quercetin in leukemia. Cancer Prev Res (Phila). 2014;7(12):1240–50.

    Article  CAS  Google Scholar 

  45. Zavadil J, Haley J, Kalluri R, Muthuswamy SK, Thompson E. Epithelial-mesenchymal transition. Cancer Res. American Society for Investigative Pathology2008;68(23):9574–7.

    Article  CAS  PubMed  Google Scholar 

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  1. Symbiosis School of Biomedical Sciences, Symbiosis International University, Gram - Lavale; Taluka - Mulshi, Pune, 412115, India

    Meghna M. Baruah, Anand P. Khandwekar & Neeti Sharma

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  1. Meghna M. Baruah
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Correspondence to Neeti Sharma.

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Meghna M. Baruah and Neeti Sharma combined first author.

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Baruah, M.M., Khandwekar, A.P. & Sharma, N. Quercetin modulates Wnt signaling components in prostate cancer cell line by inhibiting cell viability, migration, and metastases. Tumor Biol. 37, 14025–14034 (2016). https://doi.org/10.1007/s13277-016-5277-6

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