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CD137 ligand-mediated reverse signaling inhibits proliferation and induces apoptosis in non-small cell lung cancer

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Abstract

CD137 ligand (CD137L), a member of the tumor necrosis factor superfamily, is expressed on antigen-presenting cells and also on various tumor cells. Crosslinking of CD137L transmits signals that evoke different cellular responses in a variety of tumor cells. This study was designed to investigate signaling pathways activated by CD137L and its physiologic role in the progression of NSCLC. We investigated the expression of CD137L in tissues from 102 cases of human non-small cell lung cancer (NSCLC) using immunohistochemistry and analyzed the correlation with clinicopathological features using Fisher’s exact test and overall survival using Kaplan–Meier curves and the log-rank test. The effect of CD137L reverse signaling induced by recombinant human CD137-Fc protein on NSCLC cell lines was assessed using proliferation and apoptosis assays, flow cytometry and Western blotting. Positive CD137L expression was observed in 53/102 (52.0 %) of the NSCLC samples and correlated with early TNM stage (P = 0.046), well-differentiated tumors (P = 0.009) and better overall survival (P = 0.004). Moreover, induction of CD137L reverse signaling using CD137-Fc inhibited proliferation and induced apoptosis and cell cycle arrest in H1650 cells, which express high levels of CD137L; CD137L reverse signaling had no significant effects in PC9 cells, which express low levels of CD137L. In addition, CD137L reverse signaling-induced apoptosis occurred via activation of the intrinsic pathway and depended on phosphorylation of JNK. This study demonstrates a hitherto unrecognized role for CD137L reverse signaling in the development of NSCLC and indicates that CD137L has potential as a novel therapeutic target in NSCLC.

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References

  1. Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin. 2011;61(2):69–90. doi:10.3322/caac.20107.

    Article  PubMed  Google Scholar 

  2. Lee SW, Croft M. 4-1BB as a therapeutic target for human disease. Adv Exp Med Biol. 2009;647:120–9. doi:10.1007/978-0-387-89520-8_8.

    Article  CAS  PubMed  Google Scholar 

  3. Thum E, Shao Z, Schwarz H. CD137, implications in immunity and potential for therapy. Front Biosci (Landmark Ed). 2009;14:4173–88.

    Article  CAS  PubMed  Google Scholar 

  4. Wang C, Lin GH, McPherson AJ, Watts TH. Immune regulation by 4-1BB and 4-1BBL: complexities and challenges. Immunol Rev. 2009;229(1):192–215. doi:10.1111/j.1600-065X.2009.00765.x.

    Article  CAS  PubMed  Google Scholar 

  5. Shao Z, Schwarz H. CD137 ligand, a member of the tumor necrosis factor family, regulates immune responses via reverse signal transduction. J Leukoc Biol. 2011;89(1):21–9. doi:10.1189/jlb.0510315.

    Article  CAS  PubMed  Google Scholar 

  6. Langstein J, Michel J, Schwarz H. CD137 induces proliferation and endomitosis in monocytes. Blood. 1999;94(9):3161–8.

    CAS  PubMed  Google Scholar 

  7. Langstein J, Schwarz H. Identification of CD137 as a potent monocyte survival factor. J Leukoc Biol. 1999;65(6):829–33.

    CAS  PubMed  Google Scholar 

  8. Kwajah MMS, Schwarz H. CD137 ligand signaling induces human monocyte to dendritic cell differentiation. Eur J Immunol. 2010;40(7):1938–49. doi:10.1002/eji.200940105.

    Article  Google Scholar 

  9. Ju S, Ge Y, Qiu H, Lu B, Qiu Y, Fu J, et al. A novel approach to induce human DCs from monocytes by triggering 4-1BBL reverse signaling. Int Immunol. 2009;21(10):1135–44. doi:10.1093/intimm/dxp077.

    Article  CAS  PubMed  Google Scholar 

  10. Ju SW, Ju SG, Wang FM, Gu ZJ, Qiu YH, Yu GH, et al. A functional anti-human 4-1BB ligand monoclonal antibody that enhances proliferation of monocytes by reverse signaling of 4-1BBL. Hybrid Hybridomics. 2003;22(5):333–8. doi:10.1089/153685903322538872.

    Article  CAS  PubMed  Google Scholar 

  11. Michel J, Pauly S, Langstein J, Krammer PH, Schwarz H. CD137-induced apoptosis is independent of CD95. Immunology. 1999;98(1):42–6.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  12. Baessler T, Charton JE, Schmiedel BJ, Grunebach F, Krusch M, Wacker A, et al. CD137 ligand mediates opposite effects in human and mouse NK cells and impairs NK-cell reactivity against human acute myeloid leukemia cells. Blood. 2010;115(15):3058–69. doi:10.1182/blood-2009-06-227934.

    Article  CAS  PubMed  Google Scholar 

  13. Palma C, Binaschi M, Bigioni M, Maggi CA, Goso C. CD137 and CD137 ligand constitutively coexpressed on human T and B leukemia cells signal proliferation and survival. Int J Cancer J Int Cancer. 2004;108(3):390–8. doi:10.1002/ijc.11574.

    Article  CAS  Google Scholar 

  14. Gullo C, Koh LK, Pang WL, Ho KT, Tan SH, Schwarz H. Inhibition of proliferation and induction of apoptosis in multiple myeloma cell lines by CD137 ligand signaling. PLoS One. 2010;5(5):e10845. doi:10.1371/journal.pone.0010845.

    Article  PubMed Central  PubMed  Google Scholar 

  15. Dimberg J, Hugander A, Wagsater D. Expression of CD137 and CD137 ligand in colorectal cancer patients. Oncol Rep. 2006;15(5):1197–200.

    CAS  PubMed  Google Scholar 

  16. Salih HR, Kosowski SG, Haluska VF, Starling GC, Loo DT, Lee F, et al. Constitutive expression of functional 4-1BB (CD137) ligand on carcinoma cells. J Immunol. 2000;165(5):2903–10.

    Article  CAS  PubMed  Google Scholar 

  17. Wang Q, Zhang P, Zhang Q, Wang X, Li J, Ma C, et al. Analysis of CD137 and CD137L expression in human primary tumor tissues. Croat Med J. 2008;49(2):192–200. doi:10.3325/cmj.2008.2.192.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  18. Green DR, Kroemer G. The pathophysiology of mitochondrial cell death. Science. 2004;305(5684):626–9. doi:10.1126/science.1099320.

    Article  CAS  PubMed  Google Scholar 

  19. Kwon B. CD137–CD137 ligand interactions in inflammation. Immune Netw. 2009;9(3):84–9. doi:10.4110/in.2009.9.3.84.

    Article  PubMed Central  PubMed  Google Scholar 

  20. Li G, Wu X, Zhang F, Li X, Sun B, Yu Y, et al. Triple expression of B7-1, B7-2 and 4-1BBL enhanced antitumor immune response against mouse H22 hepatocellular carcinoma. J Cancer Res Clin Oncol. 2011;137(4):695–703. doi:10.1007/s00432-010-0905-9.

    Article  CAS  PubMed  Google Scholar 

  21. Brat DJ, Bellail AC, Van Meir EG. The role of interleukin-8 and its receptors in gliomagenesis and tumoral angiogenesis. Neuro Oncol. 2005;7(2):122–33. doi:10.1215/S1152851704001061.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  22. Pauly S, Broll K, Wittmann M, Giegerich G, Schwarz H. CD137 is expressed by follicular dendritic cells and costimulates B lymphocyte activation in germinal centers. J Leukoc Biol. 2002;72(1):35–42.

    CAS  PubMed  Google Scholar 

  23. Schwarz H, Blanco FJ, von Kempis J, Valbracht J, Lotz M. ILA, a member of the human nerve growth factor/tumor necrosis factor receptor family, regulates T-lymphocyte proliferation and survival. Blood. 1996;87(7):2839–45.

    CAS  PubMed  Google Scholar 

  24. Hengartner MO. The biochemistry of apoptosis. Nature. 2000;407(6805):770–6. doi:10.1038/35037710.

    Article  CAS  PubMed  Google Scholar 

  25. Bak Y, Ham S, Baatartsogt O, Jung SH, Choi KD, Han TY, et al. A1E inhibits proliferation and induces apoptosis in NCI-H460 lung cancer cells via extrinsic and intrinsic pathways. Mol Biol Rep. 2013;40(7):4507–19. doi:10.1007/s11033-013-2544-0.

    Article  CAS  PubMed  Google Scholar 

  26. Dejean LM, Martinez-Caballero S, Manon S, Kinnally KW. Regulation of the mitochondrial apoptosis-induced channel, MAC, by BCL-2 family proteins. Biochim Biophys Acta. 2006;1762(2):191–201. doi:10.1016/j.bbadis.2005.07.002.

    Article  CAS  PubMed  Google Scholar 

  27. Jiang L, Luo M, Liu D, Chen B, Zhang W, Mai L, et al. BAD overexpression inhibits cell growth and induces apoptosis via mitochondrial-dependent pathway in non-small cell lung cancer. Cancer cell Int. 2013;13(1):53. doi:10.1186/1475-2867-13-53.

    Article  PubMed Central  PubMed  Google Scholar 

  28. Shamas-Din A, Kale J, Leber B, Andrews DW. Mechanisms of action of Bcl-2 family proteins. Cold Spring Harb Perspect Biol. 2013;5(4):a008714. doi:10.1101/cshperspect.a008714.

    Article  PubMed Central  PubMed  Google Scholar 

  29. Reddy KB, Nabha SM, Atanaskova N. Role of MAP kinase in tumor progression and invasion. Cancer Metastasis Rev. 2003;22(4):395–403.

    Article  CAS  PubMed  Google Scholar 

  30. Ravindran J, Gupta N, Agrawal M, Bala Bhaskar AS, Lakshmana Rao PV. Modulation of ROS/MAPK signaling pathways by okadaic acid leads to cell death via, mitochondrial mediated caspase-dependent mechanism. Apoptosis : Int J Program Cell Death. 2011;16(2):145–61. doi:10.1007/s10495-010-0554-.

    Article  CAS  Google Scholar 

  31. Lee HK, Park GB, Kim YS, Song H, Broaddus VC, Hur DY. Ligation of CM1 enhances apoptosis of lung cancer cells through different mechanisms in conformity with EGFR mutation. Int J Oncol. 2013;42(2):469–77. doi:10.3892/ijo.2012.1731.

    PubMed Central  CAS  PubMed  Google Scholar 

  32. Xia Z, Dickens M, Raingeaud J, Davis RJ, Greenberg ME. Opposing effects of ERK and JNK-p38 MAP kinases on apoptosis. Science. 1995;270(5240):1326–31.

    Article  CAS  PubMed  Google Scholar 

  33. Söllner L, Shaqireen DOKMM, Wu JT, Schwarz H. Signal transduction mechanisms of CD137 ligand in human monocytes. Cell Signal. 2007;19(9):1899–908. doi:10.1016/j.cellsig.2007.04.014.

    Article  PubMed  Google Scholar 

  34. Lei K, Nimnual A, Zong WX, Kennedy NJ, Flavell RA, Thompson CB, et al. The Bax subfamily of Bcl2-related proteins is essential for apoptotic signal transduction by c-Jun NH(2)-terminal kinase. Mol Cell Biol. 2002;22(13):4929–42.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This work was supported by the grant from National Natural Science Foundation of China (H1601, program 81071643). We thank Elixigen Corporation (Huntington Beach, California, USA) for helping in proofreading and editing the English of final manuscript.

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Authors and Affiliations

  1. Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, Jiangsu, China

    Yingying Qian, Dong Pei, Ting Cheng, Changling Wu, Xiaofeng Chen, Yiqian Liu, Hong Shen & Yongqian Shu

  2. Department of Oncology, Geriatric Institute of Jiangsu Province, 65 Jiangsu Road, Nanjing, 210009, Jiangsu, China

    Xiaolin Pu

  3. Department of Pathogen Biology and Immunology, Jiangsu Key Laboratory of Pathogen Biology, Nanjing Medical University, 140 Hanzhong Road, Nanjing, 210029, Jiangsu, China

    Weiwei Zhang

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  1. Yingying Qian
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Correspondence to Yongqian Shu.

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Qian, Y., Pei, D., Cheng, T. et al. CD137 ligand-mediated reverse signaling inhibits proliferation and induces apoptosis in non-small cell lung cancer. Med Oncol 32, 44 (2015). https://doi.org/10.1007/s12032-015-0499-9

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