Asian Pacific Journal of Cancer Prevention

Asian Pacific Journal of Cancer Prevention (아시아태평양암예방학회)
권호 표지
DOI QR코드

DOI QR Code

FNC, a Novel Nucleoside Analogue, Blocks Invasion of Aggressive Non-Hodgkin Lymphoma Cell Lines Via Inhibition of the Wnt/β-Catenin Signaling Pathway

  • Zhang, Yan (Academy of Medical and Pharmaceutical Sciences, Zhengzhou University) ;
  • Wang, Chen-Ping (School of Pharmaceutical Sciences, Zhengzhou University) ;
  • Ding, Xi-Xi (School of Pharmaceutical Sciences, Zhengzhou University) ;
  • Wang, Ning (Academy of Medical and Pharmaceutical Sciences, Zhengzhou University) ;
  • Ma, Fang (Academy of Medical and Pharmaceutical Sciences, Zhengzhou University) ;
  • Jiang, Jin-Hua (Academy of Medical and Pharmaceutical Sciences, Zhengzhou University) ;
  • Wang, Qing-Duan (Academy of Medical and Pharmaceutical Sciences, Zhengzhou University) ;
  • Chang, Jun-Biao (The College of Chemistry and Molecular Engineering, Zhengzhou University)
  • Published : 2014.08.30
Download PDF
⟨ Previous Next ⟩

Abstract

Chemotherapy is the primary therapy for malignant lymphoma (ML). However, the clinical outcome is still far from satisfactory. Consequently, an understanding of the mechanism of modulating cancer cell invasion, migration and metastasis is important for the development of more effective chemotherapeutic agents. FNC, 2'-deoxy-2'-${\beta}$-fluoro-4'-azidocytidine, a novel cytidine analogue, has demonstrated significantly inhibitory effects on proliferation of several non-Hodgkin lymphoma (NHL) cell lines. A previous study indicated that FNC effectively inhibited the growth of Raji and JeKo-1 cells in dose-time dependent effects with $IC_{50}$ values of $0.2{\mu}M$ and $0.097{\mu}M$, respectively. This study was focused on investigating the anti-invasive properties of FNC on NHL cells and its potential mechanisms of action. Cell adhesion and transwell chamber assays were utilized to investigate the anti-invasive effects of FNC on Raji and JeKo-1 cells. Real-time PCR and Western blotting were employed to qualify the expression of ${\beta}$-catenin, the glycogen synthase kinase-3 beta (GSK-$3{\beta}$), E-cadherin vascular endothelial growth factor (VEGF), matrix metalloproteinase-2 (MMP-2) and matrix metalloproteinase-9 (MMP-9). The results revealed that FNC remarkably inhibited the adhesion, migration and invasion of two human aggressive non-Hodgkin lymphoma cell lines in a dose dependent manner. Furthermore, ${\beta}$-catenin, MMP-2, MMP-9, VEGF mRNA and protein levels were decreased after FNC treatment, while GSK-$3{\beta}$ and E-cadherin increased. Our studies thus provide evidence and a rationale that FNC may offer an effective chemotherapeutic agent by regulating the invasion and metastasis of aggressive non-Hodgkin lymphoma via inhibition of the Wnt/${\beta}$-catenin signaling pathway.

Keywords

References

  1. Bae GY, Choi SJ, Lee JS, et al (2013). Loss of E-cadherin activates EGFR-MEK/ERK signaling, which promotes invasion via the ZEB1/MMP2 axis in non-small cell lung cancer. Oncotarget, 4, 2512-22.
  2. Canel M, Serrels A, Frame MC, et al (2013). E-cadherin-integrin crosstalk in cancer invasion and metastasis. J Cell Sci, 126, 393-401. https://doi.org/10.1242/jcs.100115
  3. Gan GG, Subramaniam R, Bee PC, et al (2014). Impact of inadequate doses of rituximab in the treatment of diffuse large B cell lymphoma in Malaysian patients. Asian Pac J Cancer Prev, 15, 1703-6. https://doi.org/10.7314/APJCP.2014.15.4.1703
  4. Gelebart P, Anand M, Armanious H, et al (2008). Constitutive activation of the Wnt canonical pathway in mantle cell lymphoma. Blood, 112, 5171-9. https://doi.org/10.1182/blood-2008-02-139212
  5. Harrison AM, Thalji NM, Greenberg AJ, et al (2014). Rituximab for non-Hodgkin's lymphoma: a story of rapid success in translation. Clin Transl Sci, 7, 82-6. https://doi.org/10.1111/cts.12111
  6. Herszenyi L, Hritz I, Lakatos G, et al (2012). The behavior of matrix metalloproteinases and their inhibitors in colorectal cancer. Int J Mol Sci, 13, 13240-63. https://doi.org/10.3390/ijms131013240
  7. Heuberger J, Birchmeier W (2010). Interplay of cadherinmediated cell adhesion and canonical Wnt signaling. Cold Spring Harb Perspect Biol, 2, 2915. https://doi.org/10.1101/cshperspect.a002915
  8. Hodge LS, Taub ME, Tracy TS. (2011). Effect of its deaminated metabolite, 2', 2'-difluorodeoxyuridine, on the transport and toxicity of gemcitabine in HeLa cells. Biochem Pharmacol, 81, 950-6. https://doi.org/10.1016/j.bcp.2011.01.016
  9. Jemal A, Bray F, Center MM, et al (2011). Global cancer statistics. CA Cancer J Clin, 61, 69-90. https://doi.org/10.3322/caac.20107
  10. Jordheim LP, Durantel D, Zoulim F, et al (2013). Advances in the development of nucleoside and nucleotide analogues for cancer and viral diseases. Nat Rev Drug Discov, 12, 447-64. https://doi.org/10.1038/nrd4010
  11. Kim, H, Yoo SB, Sun P, et al (2013). Alteration of the E-cadherin/ beta-catenin complex is an independent poor prognostic factor in lung adenocarcinoma. Korean J Pathol, 47, 44-51. https://doi.org/10.4132/KoreanJPathol.2013.47.1.44
  12. Kim S, Kim SH, Hur SM, et al (2009). Silibinin prevents TPAinduced MMP-9 expression by down-regulation of COX-2 in human breast cancer cells. J Ethnopharmacol, 126, 252-7. https://doi.org/10.1016/j.jep.2009.08.032
  13. Klumpp K, Kalayanov G, Ma H, et al (2008). 2'-deoxy-4'-azido nucleoside analogs are highly potent inhibitors of hepatitis C virus replication despite the lack of 2'-alpha-hydroxyl groups. J Biol Chem, 283, 2167-75. https://doi.org/10.1074/jbc.M708929200
  14. Kossakowska AE, Edwards DR, Prusinkiewicz C, et al (1999). Interleukin-6 regulation of matrix metalloproteinase (MMP- 2 and MMP-9) and tissue inhibitor of metalloproteinase (TIMP-1) expression in malignant non-Hodgkin's lymphomas. Blood, 94, 2080-9.
  15. Leow PC, Bahety P, Boon CP, et al (2014). Functionalized curcumin analogs as potent modulators of the Wnt/betacatenin signaling pathway. Eur J Med Chem, 71, 67-80. https://doi.org/10.1016/j.ejmech.2013.10.073
  16. Liu W, Zhang L, Zhou H, et al (2013). Synthesis of novel nucleoside analogue phosphorothioamidate prodrugs and in vitro anticancer evaluation against RKO human colon carcinoma cells. Nucleosides Nucleotides Nucleic Acids, 32, 161-73. https://doi.org/10.1080/15257770.2013.770523
  17. Mehner C, Hockla A, Miller E, et al (2014). Tumor cell-produced matrix metalloproteinase 9 (MMP-9) drives malignant progression and metastasis of basal-like triple negative breast cancer. Oncotarget, 5, 2737-49.
  18. Peng ZH, Wan DS, Li LR, et al (2011). Expression of COX-2, MMP-2 and VEGF in stage II and III colorectal cancer and the clinical significance. Hepatogastroenterology, 58, 369-76.
  19. Rao C, Lin SL, Wen H, et al (2013). Crosstalk between canonical TGF-beta/Smad and Wnt/beta-catenin signaling pathway. Zhejiang Da Xue Xue Bao Yi Xue Ban, 42, 591-6.
  20. Saarelainen SK, Staff S, Peltonen N, et al (2014). Endoglin, VEGF, and its receptors in predicting metastases in endometrial carcinoma. Tumour Biol, 35, 4651-7. https://doi.org/10.1007/s13277-014-1609-6
  21. Saito-Diaz K, Chen TW, Wang X, et al (2013). The way Wnt works: components and mechanism. Growth Factors, 31, 1-31. https://doi.org/10.3109/08977194.2012.752737
  22. Tuncbilek M, Guven EB, Onder T, et al (2012). Synthesis of novel 6- (4-substituted piperazine-1-yl)-9- (beta-D-ribofuranosyl) purine derivatives, which lead to senescence-induced cell death in liver cancer cells. J Med Chem, 55, 3058-65. https://doi.org/10.1021/jm3001532
  23. Wang J, Wang X, Gao C, et al (2013). The pyrimidine analog FNC inhibits cell proliferation and viral protein synthesis in HTLV1infected cells. Mol Med Rep, 7, 1656-60.
  24. Wang Q, Liu X, Wang Q, et al (2011). FNC, a novel nucleoside analogue inhibits cell proliferation and tumor growth in a variety of human cancer cells. Biochem Pharmacol, 81, 848-55. https://doi.org/10.1016/j.bcp.2011.01.001
  25. Xiao R, Zhao Y, Wang LJ, et al (2011). Effects of Roundabout 5 on adhesion, invasion and potential motility of human tongue carcinoma Tb cells. Chin Med J, 124, 2367-71.
  26. Yoh KA, Lee HS, Park LC, et al (2014). The prognostic significance of elevated levels of serum ferritin before chemotherapy in patients with non-Hodgkin lymphoma. Clin Lymphoma Myeloma Leuk, 14, 43-9. https://doi.org/10.1016/j.clml.2013.09.008
  27. Yuan JB, Yang LY, Tang ZY, et al (2012). Down-regulation of EZH2 by RNA interference inhibits proliferation and invasion of ACHN cells via the Wnt/beta- catenin pathway. Asian Pac J Cancer Prev, 13, 6197-201. https://doi.org/10.7314/APJCP.2012.13.12.6197
  28. Zhang Y, Cheng X, Huang G, et al (2013). Effect of new nucleoside analogue FNC on proliferation, apoptosis and expressions of Bcl-6, PRDM1, C-myc in cell line Raji. J Zhengzhou University, 4, 450-4.
  29. Zheng L, Wang Q, Yang X, et al (2012). Antiviral activity of FNC, 2'-deoxy-2'-beta-fluoro-4'-azidocytidine, against human and duck HBV replication. Antivir Ther, 17, 679-87. https://doi.org/10.3851/IMP2094
  30. Zhou Y, Zhang Y, Yang X, et al (2012). Novel nucleoside analogue FNC is effective against both wild-type and lamivudine-resistant HBV clinical isolates. Antivir Ther, 17, 1593-9. https://doi.org/10.3851/IMP2292

Cited by

  1. FNC efficiently inhibits mantle cell lymphoma growth vol.12, pp.3, 2017, https://doi.org/10.1371/journal.pone.0174112