NFATc1 activation promotes the invasion of U251 human glioblastoma multiforme cells through COX-2

Wang,Laizang; Wang,Zhi; Li,Jianhua; Zhang,Weiguang; Ren,Fubin; Yue,Wu

doi:10.3892/ijmm.2015.2124

NFATc1 activation promotes the invasion of U251 human glioblastoma multiforme cells through COX-2

Authors:
- Laizang Wang
- Zhi Wang
- Jianhua Li
- Weiguang Zhang
- Fubin Ren
- Wu Yue
View Affiliations

Affiliations: Department of Neurosurgery, Fourth Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, P.R. China
Published online on: March 4, 2015 https://doi.org/10.3892/ijmm.2015.2124
Pages: 1333-1340

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Recent studies have revealed that the nuclear factor of activated T-cells (NFAT) is a transcription factor that is highly expressed in aggressive cancer cells and tissues, and mediates invasion through the transcriptional induction of pro-invasion and pro-migration genes. However, the mechanisms through which nuclear factor of activated T-cells, cytoplasmic 1 (NFATc1), in particular, translocates to the nucleus and regulates the invasion of human glioblastoma multiforme (GBM) cells have not yet been fully elucidated. In the present study, to investigate the role of NFATc1 in GBM cells, we established a U251 cell line expressing a constitutively active form of NFATc1 (CA-NFATc1). On the other hand, RNA interference was used to knock down NFATc1 expression in the U251 cell line. Our results demonstrated that the expression of CA-NFATc1 promoted cancer cell invasion, while small interfering RNA (siRNA) against NFATc1 successfully inhibited the invasion ability of the U251 cell line. Moreover, we demonstrated that NFATc1 promoted U251 cell invasion through the induction of cyclooxygenase-2 (COX‑2). NFAT transcriptionally regulates the induction of COX-2 induction in U251 cells and binds to the promoter. We also demonstrated that a large proportion of GBM specimens expressed NFATc1. NFATc1 expression increased according to the histopathological grade of the glioma. However, no NFATc1 staining was observed in the non-neoplastic brain tissues. These findings suggest that the inhibition of the activation of the NFATc1 pathway is an effective therapeutic strategy for the clinical management of GBM.

View Figures

View References

1	Pan MG, Xiong Y and Chen F: NFAT gene family in inflammation and cancer. Curr Mol Med. 13:543–554. 2013. View Article : Google Scholar :
2	Daniel C, Gerlach K, Väth M, Neurath MF and Weigmann B: Nuclear factor of activated T cells – a transcription factor family as critical regulator in lung and colon cancer. Int J Cancer. 134:1767–1775. 2014. View Article : Google Scholar
3	Jauliac S, Lopez-Rodriguez C, Shaw LM, Brown LF, Rao A and Toker A: The role of NFAT transcription factors in integrin-mediated carcinoma invasion. Nat Cell Biol. 4:540–544. 2002. View Article : Google Scholar : PubMed/NCBI
4	Medyouf H, Alcalde H, Berthier C, et al: Targeting calcineurin activation as a therapeutic strategy for T-cell acute lymphoblastic leukemia. Nat Med. 13:736–741. 2007. View Article : Google Scholar : PubMed/NCBI
5	Yang P, Cartwright CA, Li J, et al: Arachidonic acid metabolism in human prostate cancer. Int J Oncol. 41:1495–1503. 2012.PubMed/NCBI
6	Castro-Sánchez L, Agra N, Llorente Izquierdo C, et al: Regulation of 15-hydroxyprostaglandin dehydrogenase expression in hepatocellular carcinoma. Int J Biochem Cell Biol. 45:2501–2511. 2013. View Article : Google Scholar : PubMed/NCBI
7	Smith WL, DeWitt DL and Garavito RM: Cyclooxygenases: structural, cellular, and molecular biology. Annu Rev Biochem. 69:145–182. 2000. View Article : Google Scholar : PubMed/NCBI
8	Tomozawa S, Tsuno NH, Sunami E, et al: Cyclooxygenase-2 overexpression correlates with tumour recurrence, especially haematogenous metastasis, of colorectal cancer. Br J Cancer. 83:324–328. 2000. View Article : Google Scholar : PubMed/NCBI
9	Soslow RA, Dannenberg AJ, Rush D, et al: COX-2 is expressed in human pulmonary, colonic, and mammary tumors. Cancer. 89:2637–2645. 2000. View Article : Google Scholar
10	Denkert C, Kobel M, Pest S, et al: Expression of cyclooxygenase 2 is an independent prognostic factor in human ovarian carcinoma. Am J Pathol. 160:893–903. 2002. View Article : Google Scholar : PubMed/NCBI
11	Iniguez MA, Rodriguez A, Volpert OV, Fresno M and Redondo JM: Cyclooxygenase-2: a therapeutic target in angiogenesis. Trends Mol Med. 9:73–78. 2003. View Article : Google Scholar : PubMed/NCBI
12	Chang SH, Liu CH, Conway R, et al: Role of prostaglandin E2-dependent angiogenic switch in cyclooxygenase 2-induced breast cancer progression. Proc Natl Acad Sci USA. 101:591–596. 2004. View Article : Google Scholar :
13	Myung SJ and Kim IH: Role of prostaglandins in colon cancer. Korean J Gastroenterol. 51:274–279. 2008.In Korean. PubMed/NCBI
14	Iniguez MA, Martinez-Martinez S, Punzon C, Redondo JM and Fresno M: An essential role of the nuclear factor of activated T cells in the regulation of the expression of the cyclooxygenase-2 gene in human T lymphocytes. J Biol Chem. 275:23627–23635. 2000. View Article : Google Scholar : PubMed/NCBI
15	Duque J, Fresno M and Iniguez MA: Expression and function of the nuclear factor of activated T cells in colon carcinoma cells: involvement in the regulation of cyclooxygenase-2. J Biol Chem. 280:8686–8693. 2005. View Article : Google Scholar : PubMed/NCBI
16	Crabtree GR and Olson EN: NFAT signaling: choreographing the social lives of cells. Cell. 109(Suppl): S67–79. 2002. View Article : Google Scholar : PubMed/NCBI
17	Serfling E, Avots A, Klein-Hessling S, Rudolf R, Vaeth M and Berberich-Siebelt F: NFATc1/αA: The other face of NFAT factors in lymphocytes. Cell Commun Signal. 10:162012. View Article : Google Scholar
18	Langworthy M, Zhou B, de Caestecker M, Moeckel G and Baldwin HS: NFATc1 identifies a population of proximal tubule cell progenitors. J Am Soc Nephrol. 20:311–321. 2009. View Article : Google Scholar : PubMed/NCBI
19	Cao S, Yan Y, Zhang X, et al: EGF stimulates cyclooxygenase-2 expression through the STAT5 signaling pathway in human lung adenocarcinoma A549 cells. Int J Oncol. 39:383–391. 2011.PubMed/NCBI
20	Neal JW and Clipstone NA: A constitutively active NFATc1 mutant induces a transformed phenotype in 3T3-L1 fibroblasts. J Biol Chem. 278:17246–17254. 2003. View Article : Google Scholar : PubMed/NCBI
21	Wang C, Cao S, Yan Y, et al: TLR9 expression in glioma tissues correlated to glioma progression and the prognosis of GBM patients. BMC Cancer. 10:4152010. View Article : Google Scholar : PubMed/NCBI
22	Hernandez GL, Volpert OV, Iniguez MA, et al: Selective inhibition of vascular endothelial growth factor-mediated angiogenesis by cyclosporin A: roles of the nuclear factor of activated T cells and cyclooxygenase 2. J Exp Med. 193:607–620. 2001. View Article : Google Scholar : PubMed/NCBI
23	Sugimoto T, Haneda M, Sawano H, et al: Endothelin-1 induces cyclooxygenase-2 expression via nuclear factor of activated T-cell transcription factor in glomerular mesangial cells. J Am Soc Nephrol. 12:1359–1368. 2001.PubMed/NCBI
24	Maier JA, Hla T and Maciag T: Cyclooxygenase is an immediate-early gene induced by interleukin-1 in human endothelial cells. J Biol Chem. 265:10805–10808. 1990.PubMed/NCBI
25	Herschman HR, Fletcher BS and Kujubu DA: TIS10, a mitogen-inducible glucocorticoid-inhibited gene that encodes a second prostaglandin synthase/cyclooxygenase enzyme. J Lipid Mediat. 6:89–99. 1993.PubMed/NCBI
26	Hogan PG, Chen L, Nardone J and Rao A: Transcriptional regulation by calcium, calcineurin, and NFAT. Genes Dev. 17:2205–2232. 2003. View Article : Google Scholar : PubMed/NCBI
27	Mancini M and Toker A: NFAT proteins: emerging roles in cancer progression. Nat Rev Cancer. 9:810–820. 2009. View Article : Google Scholar : PubMed/NCBI
28	Buchholz M, Schatz A, Wagner M, et al: Overexpression of c-myc in pancreatic cancer caused by ectopic activation of NFATc1 and the Ca²⁺/calcineurin signaling pathway. EMBO J. 25:3714–3724. 2006. View Article : Google Scholar : PubMed/NCBI
29	Oikawa T, Nakamura A, Onishi N, Yamada T, Matsuo K and Saya H: Acquired expression of NFATc1 downregulates E-cadherin and promotes cancer cell invasion. Cancer Res. 73:5100–5109. 2013. View Article : Google Scholar : PubMed/NCBI
30	Cressey R, Pimpa S, Tontrong W, Watananupong O and Leartprasertsuke N: Expression of cyclooxygenase-2 in colorectal adenocarcinoma is associated with p53 accumulation and hdm2 overexpression. Cancer Lett. 233:232–239. 2006. View Article : Google Scholar
31	Gately S and Li WW: Multiple roles of COX-2 in tumor angiogenesis: a target for antiangiogenic therapy. Semin Oncol. 31:2–11. 2004. View Article : Google Scholar : PubMed/NCBI
32	Ogino S, Kirkner GJ, Nosho K, et al: Cyclooxygenase-2 expression is an independent predictor of poor prognosis in colon cancer. Clin Cancer Res. 14:8221–8227. 2008. View Article : Google Scholar : PubMed/NCBI
33	Brown JR and DuBois RN: Cyclooxygenase as a target in lung cancer. Clin Cancer Res. 10:4266s–4269s. 2004. View Article : Google Scholar : PubMed/NCBI
34	Wu X, Cai M, Ji F and Lou LM: The impact of COX-2 on invasion of osteosarcoma cell and its mechanism of regulation. Cancer Cell Int. 14:272014. View Article : Google Scholar : PubMed/NCBI
35	Yiu GK and Toker A: NFAT induces breast cancer cell invasion by promoting the induction of cyclooxygenase-2. J Biol Chem. 281:12210–12217. 2006. View Article : Google Scholar : PubMed/NCBI
36	Lara-Pezzi E, Gomez-Gaviro MV, Galvez BG, et al: The hepatitis B virus X protein promotes tumor cell invasion by inducing membrane-type matrix metalloproteinase-1 and cyclooxygenase-2 expression. J Clin Invest. 110:1831–1838. 2002. View Article : Google Scholar : PubMed/NCBI
37	Fenwick SW, Toogood GJ, Lodge JP and Hull MA: The effect of the selective cyclooxygenase-2 inhibitor rofecoxib on human colorectal cancer liver metastases. Gastroenterology. 125:716–729. 2003. View Article : Google Scholar : PubMed/NCBI
38	Yao M, Kargman S, Lam EC, et al: Inhibition of cyclooxygenase-2 by rofecoxib attenuates the growth and metastatic potential of colorectal carcinoma in mice. Cancer Res. 63:586–592. 2003.PubMed/NCBI
39	Tsujii M and DuBois RN: Alterations in cellular adhesion and apoptosis in epithelial cells overexpressing prostaglandin endoperoxide synthase 2. Cell. 83:493–501. 1995. View Article : Google Scholar : PubMed/NCBI
40	Tsujii M, Kawano S and DuBois RN: Cyclooxygenase-2 expression in human colon cancer cells increases metastatic potential. Proc Natl Acad Sci USA. 94:3336–3340. 1997. View Article : Google Scholar : PubMed/NCBI
41	Mott JD and Werb Z: Regulation of matrix biology by matrix metalloproteinases. Curr Opin Cell Biol. 16:558–564. 2004. View Article : Google Scholar : PubMed/NCBI