Abstract
Non-small cell lung cancer (NSCLC) is a leading cause of cancer-related mortality worldwide. Basic fibroblast growth factor (bFGF) is up-regulated in NSCLC patients and plays an important role in tumor growth. In this paper, we attempt to evaluate the therapeutic potential of bFGF binding peptide (named as P7) using as a potent bFGF antagonist via exploration of its anti-proliferation effect on NSCLC cells. Our experiments showed that P7 peptide inhibited bFGF-stimulated proliferation of NSCLC cell lines including A549, H1299, and H460. The inhibitory mechanism of P7 involved cell cycle arrest at the G0/G1phase caused by suppression of cyclin D1, blockage of the activation of Erk1/2, P38, Akt, and inhibition of bFGF internalization. Strategies using bFGF antagonist peptides with potent anti-proliferation property may have therapeutic potential in NSCLC.
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References
Assoian RK, Schwartz MA (2001) Coordinate signaling by integrins and receptor tyrosine kinases in the regulation of G1 phase cell-cycle progression. Curr Opin Genet Dev 11(1):48–53
Bossard C, Laurell H, Van den Berghe L, Meunier S, Zanibellato C, Prats H (2003) Translokin is an intracellular mediator of FGF-2 trafficking. Nat Cell Biol 5(5):433–439. doi:10.1038/ncb979
Carney DN (2002) Lung cancer—time to move on from chemotherapy. N Engl J Med 346(2):126–128. doi:10.1056/NEJM200201103460211
Chellaiah AT, McEwen DG, Werner S, Xu J, Ornitz DM (1994) Fibroblast growth factor receptor (FGFR) 3. Alternative splicing in immunoglobulin-like domain III creates a receptor highly specific for acidic FGF/FGF-1. J Biol Chem 269(15):11620–11627
Cronauer MV, Schulz WA, Seifert HH, Ackermann R, Burchardt M (2003) Fibroblast growth factors and their receptors in urological cancers: basic research and clinical implications. Eur Urol 43(3):309–319
Cullen MH, Billingham LJ, Woodroffe CM, Chetiyawardana AD, Gower NH, Joshi R, Ferry DR, Rudd RM, Spiro SG, Cook JE, Trask C, Bessell E, Connolly CK, Tobias J, Souhami RL (1999) Mitomycin, ifosfamide, and cisplatin in unresectable non-small-cell lung cancer: effects on survival and quality of life. J Clin Oncol 17(10):3188–3194
Dailey L, Ambrosetti D, Mansukhani A, Basilico C (2005) Mechanisms underlying differential responses to FGF signaling. Cytokine Growth Factor Rev 16(2):233–247. doi:10.1016/j.cytogfr.2005.01.007
Eswarakumar VP, Lax I, Schlessinger J (2005) Cellular signaling by fibroblast growth factor receptors. Cytokine Growth Factor Rev 16(2):139–149. doi:10.1016/j.cytogfr.2005.01.001
Facchiano A, Russo K, Facchiano AM, De Marchis F, Facchiano F, Ribatti D, Aguzzi MS, Capogrossi MC (2003) Identification of a novel domain of fibroblast growth factor 2 controlling its angiogenic properties. J Biol Chem 278(10):8751–8760. doi:10.1074/jbc.M209936200
Gao N, Zhang Z, Jiang BH, Shi X (2003) Role of PI3K/AKT/mTOR signaling in the cell cycle progression of human prostate cancer. Biochem Biophys Res Commun 310(4):1124–1132
Ginsberg RJ, Rubinstein LV (1995) Randomized trial of lobectomy versus limited resection for T1 N0 non-small cell lung cancer. Lung Cancer Study Group. Ann Thorac Surg 60(3):615–622; discussion 622–623
Gridelli C, Rossi A, Maione P (2006) New antiangiogenetic agents and non-small cell lung cancer. Crit Rev Oncol Hematol 60(1):76–86. doi:10.1016/j.critrevonc.2006.01.008
Ho A, Dowdy SF (2002) Regulation of G(1) cell-cycle progression by oncogenes and tumor suppressor genes. Curr Opin Genet Dev 12(1):47–52
Hotta K, Matsuo K, Ueoka H, Kiura K, Tabata M, Tanimoto M (2004) Addition of platinum compounds to a new agent in patients with advanced non-small-cell lung cancer: a literature based meta-analysis of randomised trials. Ann Oncol 15(12):1782–1789. doi:10.1093/annonc/mdh476
Hu Z, Chen X, Zhao Y, Tian T, Jin G, Shu Y, Chen Y, Xu L, Zen K, Zhang C, Shen H (2010) Serum microRNA signatures identified in a genome-wide serum microRNA expression profiling predict survival of non-small-cell lung cancer. J Clin Oncol 28(10):1721–1726. doi:10.1200/JCO.2009.24.9342
Jemal A, Siegel R, Ward E, Murray T, Xu J, Thun MJ (2007) Cancer statistics, 2007. CA Cancer J Clin 57(1):43–66
Kremer NE, D’Arcangelo G, Thomas SM, DeMarco M, Brugge JS, Halegoua S (1991) Signal transduction by nerve growth factor and fibroblast growth factor in PC12 cells requires a sequence of src and ras actions. J Cell Biol 115(3):809–819
Lund EL, Thorsen C, Pedersen MW, Junker N, Kristjansen PE (2000) Relationship between vessel density and expression of vascular endothelial growth factor and basic fibroblast growth factor in small cell lung cancer in vivo and in vitro. Clin Cancer Res 6(11):4287–4291
Maher P (1999) p38 Mitogen-activated protein kinase activation is required for fibroblast growth factor-2-stimulated cell proliferation but not differentiation. J Biol Chem 274(25):17491–17498
Mansukhani A, Dell’Era P, Moscatelli D, Kornbluth S, Hanafusa H, Basilico C (1992) Characterization of the murine BEK fibroblast growth factor (FGF) receptor: activation by three members of the FGF family and requirement for heparin. Proc Natl Acad Sci USA 89(8):3305–3309
Marek L, Ware KE, Fritzsche A, Hercule P, Helton WR, Smith JE, McDermott LA, Coldren CD, Nemenoff RA, Merrick DT, Helfrich BA, Bunn PA Jr, Heasley LE (2009) Fibroblast growth factor (FGF) and FGF receptor-mediated autocrine signaling in non-small-cell lung cancer cells. Mol Pharmacol 75(1):196–207. doi:10.1124/mol.108.049544
Mohammadi M, Olsen SK, Ibrahimi OA (2005) Structural basis for fibroblast growth factor receptor activation. Cytokine Growth Factor Rev 16(2):107–137. doi:10.1016/j.cytogfr.2005.01.008
Ornitz DM, Xu J, Colvin JS, McEwen DG, MacArthur CA, Coulier F, Gao G, Goldfarb M (1996) Receptor specificity of the fibroblast growth factor family. J Biol Chem 271(25):15292–15297
Pirozynski M (2006) 100 years of lung cancer. Respir Med 100(12):2073–2084. doi:10.1016/j.rmed.2006.09.002
Plotnikov AN, Schlessinger J, Hubbard SR, Mohammadi M (1999) Structural basis for FGF receptor dimerization and activation. Cell 98(5):641–650
Ren M, Hong M, Liu G, Wang H, Patel V, Biddinger P, Silva J, Cowell J, Hao Z (2013) Novel FGFR inhibitor ponatinib suppresses the growth of non-small cell lung cancer cells overexpressing FGFR1. Oncol Rep 29(6):2181–2190. doi:10.3892/or.2013.2386
Ron D, Reich R, Chedid M, Lengel C, Cohen OE, Chan AM, Neufeld G, Miki T, Tronick SR (1993) Fibroblast growth factor receptor 4 is a high affinity receptor for both acidic and basic fibroblast growth factor but not for keratinocyte growth factor. J Biol Chem 268(8):5388–5394
Rusnati M, Presta M (2007) Fibroblast growth factors/fibroblast growth factor receptors as targets for the development of anti-angiogenesis strategies. Curr Pharm Des 13(20):2025–2044
Sorensen V, Nilsen T, Wiedlocha A (2006) Functional diversity of FGF-2 isoforms by intracellular sorting. BioEssays 28(5):504–514. doi:10.1002/bies.20405
Sweeney CJ, Zhu J, Sandler AB, Schiller J, Belani CP, Langer C, Krook J, Harrington D, Johnson DH (2001) Outcome of patients with a performance status of 2 in Eastern Cooperative Oncology Group Study E1594: a Phase II trial in patients with metastatic nonsmall cell lung carcinoma. Cancer 92(10):2639–2647
Takanami I, Imamura T, Hashizume T, Kikuchi K, Yamamoto Y, Yamamoto T, Kodaira S (1996) Immunohistochemical detection of basic fibroblast growth factor as a prognostic indicator in pulmonary adenocarcinoma. Jpn J Clin Oncol 26(5):293–297
Takanami I, Tanaka F, Hashizume T, Kodaira S (1997) Pulmonary adenocarcinoma angiogenesis. Int J Oncol 10(1):101–106
Thomson S, Petti F, Sujka-Kwok I, Epstein D, Haley JD (2008) Kinase switching in mesenchymal-like non-small cell lung cancer lines contributes to EGFR inhibitor resistance through pathway redundancy. Clin Exp Metastasis 25(8):843–854. doi:10.1007/s10585-008-9200-4
Tsai JC, Goldman CK, Gillespie GY (1995) Vascular endothelial growth factor in human glioma cell lines: induced secretion by EGF, PDGF-BB, and bFGF. J Neurosurg 82(5):864–873. doi:10.3171/jns.1995.82.5.0864
Volm M, Koomagi R, Mattern J, Stammler G (1997) Prognostic value of basic fibroblast growth factor and its receptor (FGFR-1) in patients with non-small cell lung carcinomas. Eur J Cancer 33(4):691–693
Werner S, Duan DS, de Vries C, Peters KG, Johnson DE, Williams LT (1992) Differential splicing in the extracellular region of fibroblast growth factor receptor 1 generates receptor variants with different ligand-binding specificities. Mol Cell Biol 12(1):82–88
Wu X, Yan Q, Huang Y, Huang H, Su Z, Xiao J, Zeng Y, Wang Y, Nie C, Yang Y, Li X (2010) Isolation of a novel basic FGF-binding peptide with potent antiangiogenetic activity. J Cell Mol Med 14(1–2):351–356. doi:10.1111/j.1582-4934.2008.00506.x
Acknowledgments
This work was supported by grants from the National Natural Science Foundation of China (30973671, 81071800), the Guangdong Provincial Science and Technology Program (2010B060900040), the Natural Science Foundation of Guangdong Province of China (9151064001000031), the Natural Science Foundation of Zhejiang Province of China (Y2090292, Y4090379), the Science and Technology Planning Project of Wenzhou (Y20090244), the Fundamental Research Funds for the Central Universities (X. Wu), Guangdong Provincial ‘‘Thousand-Hundred-Ten Talent Project’’ (X. Wu), and Key Laboratory of Functional Protein Research of Guangdong Higher Education Institutes, Jinan University.
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Wang, R., Luo, W., He, D. et al. Inhibition of Proliferation of Non-small Cell Lung Cancer Cells by a bFGF Antagonist Peptide. Int J Pept Res Ther 20, 109–115 (2014). https://doi.org/10.1007/s10989-013-9372-x
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DOI: https://doi.org/10.1007/s10989-013-9372-x