Development and Reproduction (한국발생생물학회지:발생과생식)

The Korean Society of Developmental Biology (한국발생생물학회)
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XRP44X Enhances the Cytotoxic Activity of Natural Killer Cells by Activating the c-JUN N-Terminal Kinase Signaling Pathway

  • Kim, Kwang-Soo (Dept. of Biomedical Science, College of Life Science, CHA University) ;
  • Park, Kyung-Soon (Dept. of Biomedical Science, College of Life Science, CHA University)
  • Received : 2020.01.14
  • Accepted : 2020.01.28
  • Published : 2020.03.31
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Abstract

Natural killer (NK) cells are innate lymphocytes that play an essential role in preventing cancer development by performing immune surveillance to eradicate abnormal cells. Since ex vivo expanded NK cells have cytotoxic activity against various cancers, including breast cancers, their clinical potential as immune-oncogenic therapeutics has been widely investigated. Here, we report that the pyrazole chemical XRP44X, an inhibitor of Ras/ERK activation of ELK3, stimulates NK-92MI cells to enhance cytotoxic activity against breast cancer cells. Under XRP44X stimulation, NK cells did not show notable apoptosis or impaired cell cycle progression. We demonstrated that XRP44X enhanced interferon gamma expression in NK-92MI cells. We also elucidated that potentiation of the cytotoxic activity of NK-92MI cells by XRP44X is induced by activation of the c-JUN N-terminal kinase (JNK) signaling pathway. Our data provide insight into the evaluation of XRP44X as an immune stimulant and that XRP44X is a potential candidate compound for the therapeutic development of NK cells.

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References

  1. Bauer S, Groh V, Wu J, Steinle A, Phillips JH, Lanier LL, Spies T (1999) Activation of NK cells and T cells by NKG2D, a receptor for stress-inducible MICA. Science 285:727-729. https://doi.org/10.1126/science.285.5428.727
  2. Chen J, Sun WL, Wasylyk B, Wang YP, Zheng H (2012) c-Jun N-terminal kinase mediates microtubule-depolymerizing agent-induced microtubule depolymerization and G2/M arrest in MCF-7 breast cancer cells. Anticancer Drugs 23:98-107. https://doi.org/10.1097/CAD.0b013e32834bc978
  3. Ge H, Lv X, Jin H, Tian Z, Li Y, He H (2017) The role of endovascular treatment in unruptured basilar tip aneurysms. Interv Neuroradiol 23:8-13. https://doi.org/10.1177/1591019917727400
  4. Huntington ND (2014) The unconventional expression of IL-15 and its role in NK cell homeostasis. Immunol Cell Biol 92:210-213. https://doi.org/10.1038/icb.2014.1
  5. Janeway CA, Medzhitov R (2002) Innate immune recognition. Annu Rev Immunol 20:197-216. https://doi.org/10.1146/annurev.immunol.20.083001.084359
  6. Kong SY, Kim KS, Kim J, Kim MK, Lee KH, Lee JY, Oh N, Park JI, Park JH, Heo SH, Shim SH, Lee DR, Kim KP, Park KS (2016) The ELK3-GATA3 axis orchestrates invasion and metastasis of breast cancer cells in vitro and in vivo. Oncotarget 7:65137-65146. https://doi.org/10.18632/oncotarget.11427
  7. Kumar D, Hosse J, von Toerne C, Noessner E, Nelson PJ (2009) JNK MAPK pathway regulates constitutive transcription of CCL5 by human NK cells through SP1. J immunol 182:1011-1020. https://doi.org/10.4049/jimmunol.182.2.1011
  8. Lee JH, Hur W, Hong SW, Kim JH, Kim SM, Lee EB, Yoon SK (2017) ELK3 promotes the migration and invasion of liver cancer stem cells by targeting HIF-$1{\alpha}$. Oncol Rep 37:813-822. https://doi.org/10.3892/or.2016.5293
  9. Li C, Ge B, Nicotra M, Stern JN, Kopcow HD, Chen X, Strominger JL (2008) JNK MAP kinase activation is required for MTOC and granule polarization in NKG2D-mediated NK cell cytotoxicity. Proc Natl Acad Sci USA 105:3017-3022. https://doi.org/10.1073/pnas.0712310105
  10. Rajagopalan S, Fu J, Long EO (2001) Cutting Edge: Induction of IFN-$\gamma$ production but not cytotoxicity by the killer cell Ig-like receptor KIR2DL4 (CD158d) in resting NK cells. J Immunol 167:1877-1881. https://doi.org/10.4049/jimmunol.167.4.1877
  11. Ramirez K, Chandler KJ, Spaulding C, Zandi S, Sigvardsson M, Graves BJ, Kee BL (2012) Gene deregulation and chronic activation in natural killer cells deficient in the transcription factor ETS1. Immunity 36:921-932. https://doi.org/10.1016/j.immuni.2012.04.006
  12. Rana K, Whalen M (2015) Activation of protein kinase C and protein kinase D in human natural killer cells: effects of tributyltin, dibutyltin, and tetrabromobisphenol A. Toxicol Mech Methods 25:680-688. https://doi.org/10.3109/15376516.2015.1070226
  13. Romera-Cardenas G, Thomas LM, Lopez-Cobo S, Garcia-Cuesta EM, Long EO, Reyburn HT (2016) Ionomycin treatment renders NK cells hyporesponsive. PLoS One 11:e0150998 https://doi.org/10.1371/journal.pone.0150998
  14. Semenchenko K, Wasylyk C, Cheung H, Tourrette Y, Maas P, Schalken JA, van der Pluijm G, Wasylyk B (2016) XRP44X, an inhibitor of Ras/Erk activation of the transcription factor Elk3, inhibits tumour growth and metastasis in mice. PLoS One 11:e0159531. https://doi.org/10.1371/journal.pone.0159531
  15. Sim GC, Radvanyi L (2014) The IL-2 cytokine family in cancer immunotherapy. Cytokine Growth Factor Rev 25:377-390. https://doi.org/10.1016/j.cytogfr.2014.07.018
  16. Sutherland CL, Chalupny NJ, Schooley K, VandenBos T, Kubin M, Cosman D (2002) UL16-binding proteins, novel MHC class I-related proteins, bind to NKG2D and activate multiple signaling pathways in primary NK cells. J Immunol 168:671-679. https://doi.org/10.4049/jimmunol.168.2.671
  17. Wasylyk C, Zheng H, Castell C, Debussche L, Multon MC, Wasylyk B (2008) Inhibition of the Ras-Net (Elk-3) pathway by a novel pyrazole that affects microtubules. Cancer Res 68:1275-1283. https://doi.org/10.1158/0008-5472.CAN-07-2674
  18. Yi HS, Eun HS, Lee YS, Jung JY, Park SH, Park KG, Choi HS, Suh JM, Jeong WI (2015) Treatment with 4-methylpyrazole modulated stellate cells and natural killer cells and ameliorated liver fibrosis in mice. PLoS One 10:e0127946. https://doi.org/10.1371/journal.pone.0127946