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The novel role of IL-37 in prostate cancer: evidence as a promising radiosensitizer

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Abstract

Prostate cancer (PCa) is the most common non-cutaneous cancer in men in the USA. Radiation therapy (RT) is widely considered the standard treatment for PCa. IL-37 is an IL-1 family member, and it has been extensively studied in immunity. However, no studies have been done regarding its potential as a radiosensitizer. This study is designed to investigate the direct effect of IL-37 on growth of DU145 and PC-3, two widely studied PCa cell lines, and to investigate whether IL-37 could be used as a radiosensitizer for PCa. Clonogenic survival and quick cell proliferation assays along with immunohistochemistry, TUNEL staining, and caspace-3 activity assay kits as well as RT-PCR were used in this study. Our results showed that IL-37 has little direct effect on growth of PCa. However, IL-37/RT enhanced RT-induced inhibition of cell proliferation and apoptosis in both cell lines. We further found that IL-37/RT upregulated the mRNA expression of p27, Fas, and Bax, while downregulating the mRNA expression of cdk2 in DU145 cells. These findings suggest that IL-37 has the potential to be used as a radiosensitizer for PCa and warrants further investigation.

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References

  1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2017. CA Cancer J Clin. 2017;67(1):7–30. https://doi.org/10.3322/caac.21387.

    Article  PubMed  Google Scholar 

  2. Fang Y, DeMarco VG, Nicholl MB. Resveratrol enhances radiation sensitivity in prostate cancer by inhibiting cell proliferation and promoting cell senescence and apoptosis. Cancer Sci. 2012;103(6):1090–8.

    Article  CAS  PubMed  Google Scholar 

  3. Davis MR, Zhu Z, Hansen DM, Bai Q, Fang Y. The role of IL-21 in immunity and cancer. Cancer Lett. 2015;358(2):107–14.

    Article  CAS  PubMed  Google Scholar 

  4. Boraschi D, Lucchesi D, Hainzl S, Leitner M, Maier E, Mangelberger D, et al. IL-37: a new anti-inflammatory cytokine of the IL-1 family. Eur Cytokine Netw. 2011;22(3):127–47.

    CAS  PubMed  Google Scholar 

  5. Ding VA, Zhu Z, Xiao H, Wakefield MR, Bai Q, Fang Y. The role of IL-37 in cancer. Med Oncol. 2016;33(7):68.

    Article  PubMed  Google Scholar 

  6. Abulkhir A, Samarani S, Amre D, Duval M, Haddad E, Sinnett D, et al. A protective role of IL-37 in cancer: a new hope for cancer patients. J Leukoc Biol. 2017;101(2):395–406.

    Article  CAS  PubMed  Google Scholar 

  7. Gao W, Kumar S, Lotze MT, Hanning C, Robbins PD, Gambotto A. Innate immunity mediated by the cytokine IL-1 homologue 4 (IL-1H4/IL-1F7) induces IL-12-dependent adaptive and profound antitumor immunity. J Immunol. 2003;170(1):107–13.

    Article  CAS  PubMed  Google Scholar 

  8. Nold MF, Nold-Petry CA, Zepp JA, Palmer BE, Bufler P, Dinarello CA. IL-37 is a fundamental inhibitor of innate immunity. Nat Immunol. 2010;11(11):1014–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Wang S, An W, Yao Y, Chen R, Zheng X, Yang W, et al. Interleukin 37 expression inhibits STAT3 to suppress the proliferation and invasion of human cervical cancer cells. J Cancer. 2015;6(10):962.

    Article  PubMed  PubMed Central  Google Scholar 

  10. W-q Wang, Zhao D, Zhou Y-s Hu, X-y Sun Z-n, Yu G, et al. Transfer of the IL-37b gene elicits anti-tumor responses in mice bearing 4T1 breast cancer. Acta Pharmacol Sin. 2015;36(4):528–34.

    Article  Google Scholar 

  11. Jiang Y, Wang Y, Liang L, Gao Y, Chen J, Sun Y, et al. IL-37 mediates the antitumor activity in renal cell carcinoma. Med Oncol. 2015;32(11):250.

    Article  CAS  PubMed  Google Scholar 

  12. Fang Y, Herrick EJ, Nicholl MB. A possible role for perforin and granzyme B in resveratrol-enhanced radiosensitivity of prostate cancer. J Androl. 2012;33(4):752–60.

    Article  CAS  PubMed  Google Scholar 

  13. Fang Y, Zhao L, Xiao H, Cook KM, Bai Q, Herrick EJ, et al. IL-33 acts as a foe to MIA PaCa-2 pancreatic cancer. Med Oncol. 2017;34(2):23.

    Article  PubMed  Google Scholar 

  14. Zhu Z, Davidson KT, Brittingham A, Wakefield MR, Bai Q, Xiao H, et al. Trichomonas vaginalis: a possible foe to prostate cancer. Med Oncol. 2016;33(10):115.

    Article  PubMed  Google Scholar 

  15. Leith JT. In vitro radiation sensitivity of the LNCaP prostatic tumor cell line. Prostate. 1994;24(3):119–24.

    Article  CAS  PubMed  Google Scholar 

  16. Lee S, Margolin K. Cytokines in cancer immunotherapy. Cancers. 2011;3(4):3856–93.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Carroll AG, Voeller HJ, Sugars L, Gelmann EP. p53 oncogene mutations in three human prostate cancer cell lines. Prostate. 1993;23(2):123–34.

    Article  CAS  PubMed  Google Scholar 

  18. Sun Y, Clair DKS, Fang F, Warren GW, Rangnekar VM, Crooks PA, et al. The radiosensitization effect of parthenolide in prostate cancer cells is mediated by nuclear factor-κB inhibition and enhanced by the presence of PTEN. Mol Cancer Ther. 2007;6(9):2477–86.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. van Bokhoven A, Varella-Garcia M, Korch C, Johannes WU, Smith EE, Miller HL, et al. Molecular characterization of human prostate carcinoma cell lines. Prostate. 2003;57(3):205–25.

    Article  PubMed  Google Scholar 

  20. Nicholl MB, Chen X, Qin C, Bai Q, Zhu Z, Davis MR, et al. IL-32α has differential effects on proliferation and apoptosis of human melanoma cell lines. J Surg Oncol. 2016;113(4):364–9.

    Article  CAS  PubMed  Google Scholar 

  21. Fang Y, Chen X, Bai Q, Qin C, Mohamud AO, Zhu Z, et al. IL-9 inhibits HTB-72 melanoma cell growth through upregulation of p21 and TRAIL. J Surg Oncol. 2015;111(8):969–74.

    Article  CAS  PubMed  Google Scholar 

  22. Smith DE, Renshaw BR, Ketchem RR, Kubin M, Garka KE, Sims JE. Four new members expand the interleukin-1 superfamily. J Biol Chem. 2000;275(2):1169–75.

    Article  CAS  PubMed  Google Scholar 

  23. Dinarello CA, editor. Overview of the interleukin-1 family of ligands and receptors. Seminars in immunology. Amsterdam: Elsevier; 2013.

    Google Scholar 

  24. Johnson D, Walker C. Cyclins and cell cycle checkpoints. Annu Rev Pharmacol Toxicol. 1999;39:295–312.

    Article  CAS  PubMed  Google Scholar 

  25. Thompson CB. Apoptosis in the pathogenesis and treatment of disease. Science. 1995;267(5203):1456–62.

    Article  CAS  PubMed  Google Scholar 

  26. Sherr CJ. G1 phase progression: cycling on cue. Cell. 1994;79(4):551–5.

    Article  CAS  PubMed  Google Scholar 

  27. Ohtsubo M, Theodoras AM, Schumacher J, Roberts JM, Pagano M. Human cyclin E, a nuclear protein essential for the G1-to-S phase transition. Mol Cell Biol. 1995;15(5):2612–24.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Zhang D, Li X, Chen C, Li Y, Zhao L, Jing Y, et al. Attenuation of p38-mediated miR-1/133 expression facilitates myoblast proliferation during the early stage of muscle regeneration. PLoS ONE. 2012;7(7):e41478. https://doi.org/10.1371/journal.pone.0041478.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Zhu Z, Zhang D, Lee H, Menon AA, Wu J, Hu K, et al. Macrophage-derived apoptotic bodies promote the proliferation of the recipient cells via shuttling microRNA-221/222. J Leukoc Biol. 2017;101(6):1349–59.

    Article  CAS  PubMed  Google Scholar 

  30. Zhang H, Xu Q, Krajewski S, Krajewska M, Xie Z, Fuess S, et al. BAR: an apoptosis regulator at the intersection of caspases and Bcl-2 family proteins. Proc Natl Acad Sci. 2000;97(6):2597–602.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Funding

This study was partially supported by grants from Des Moines University for Yujiang Fang (Iowa Science Foundation Grant ISF 16-8, IOER 05-14-01, IOER 112-3749 and IOER 112-3104).

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Authors and Affiliations

  1. Department of Microbiology and Immunology, Des Moines University, Des Moines, IA, 50312, USA

    Vivi A. Ding, Timothy A. Steele, Huaping Xiao, Dean Balabanov & Yujiang Fang

  2. Department of Surgery, University of Missouri School of Medicine, Columbia, MO, 65212, USA

    Ziwen Zhu, Mark R. Wakefield & Yujiang Fang

  3. The Affiliated Hospital of Xiangnan University, Chenzhou, Hunan, China

    Huaping Xiao

Authors
  1. Vivi A. Ding
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  2. Ziwen Zhu
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  3. Timothy A. Steele
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  4. Mark R. Wakefield
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  5. Huaping Xiao
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  6. Dean Balabanov
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  7. Yujiang Fang
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Contributions

VAD and YF conceived and designed this study. VAD, ZZ, TAS, MRW, HX, DB, and YF performed experiments. VAD and YF analyzed and interpreted the data. VAD wrote the draft, and YF made critical revision. All authors approved the final version of the manuscript.

Corresponding author

Correspondence to Yujiang Fang.

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The authors declare that they have no conflict of interest.

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This article does not contain any studies with human participants or animals performed by any of the authors.

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Ding, V.A., Zhu, Z., Steele, T.A. et al. The novel role of IL-37 in prostate cancer: evidence as a promising radiosensitizer. Med Oncol 35, 6 (2018). https://doi.org/10.1007/s12032-017-1070-7

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  • DOI: https://doi.org/10.1007/s12032-017-1070-7

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