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10.1002/1878-0261.12135

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suck abstract from ncbi


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pmid28865178
      Mol+Oncol 2018 ; 12 (3 ): 269-286
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  • Inhibition of IL-6-JAK/Stat3 signaling in castration-resistant prostate cancer cells enhances the NK cell-mediated cytotoxicity via alteration of PD-L1/NKG2D ligand levels #MMPMID28865178
  • Xu L ; Chen X ; Shen M ; Yang DR ; Fang L ; Weng G ; Tsai Y ; Keng PC ; Chen Y ; Lee SO
  • Mol Oncol 2018[Mar]; 12 (3 ): 269-286 PMID28865178 show ga
  • To investigate whether IL-6 signaling affects the susceptibility of castration-resistant prostate cancer (CRPC) cells to cytotoxic action of natural killer (NK) cells, CRPC cell lines (having different IL-6 levels) were developed by lentiviral transduction. While observing no secreted IL-6 level in parental C4-2 and CWR22Rv1 cells, we found the IL-6 expression/secretion in these cells was induced after the transduction process and the IL-6 level difference in C4-2siIL-6/sc and CWR22siIL-6/sc cell CRPC cell sets could be detected. We then found that IL-6-knockdown cells were more susceptible to NK cell cytotoxicity than control cells due to lowered programmed death receptor ligand 1 (PD-L1) and increased NK group 2D (NKG2D) ligand levels. In animal studies, to concur with the in vitro results, we found that IL-6-expressing cell-derived tumors were more resistant to NK cell action than the tumors of IL-6-knockdown cells. Further, we discovered that JAK-Stat3 is the most critical IL-6 downstream signaling that modulates PD-L1/NKG2D ligand levels in CRPC cells. Furthermore, inhibition of the JAK or Stat3 signaling effectively increased the susceptibility of C4-2sc and CWRsc cells to NK cell cytotoxicity. We observed the most effective cytotoxicity when the PD-L1 Ab and JAK inhibitor (or Stat 3 inhibitor) were used together. These results suggest that the strategy of targeting IL-6 signaling (or its downstream signaling) may enhance the NK cell-mediated immune action to CRPC tumors, thus yielding clinical implications in developing future immunotherapeutics of exploiting this strategy to treat patients with CRPC.
  • |*Cytotoxicity, Immunologic [MESH]
  • |Animals [MESH]
  • |B7-H1 Antigen/genetics/*metabolism [MESH]
  • |Cell Line, Tumor [MESH]
  • |GPI-Linked Proteins/genetics/metabolism [MESH]
  • |Heterografts [MESH]
  • |Humans [MESH]
  • |Immunotherapy [MESH]
  • |Intercellular Signaling Peptides and Proteins/genetics/*metabolism [MESH]
  • |Interleukin-6/*antagonists & inhibitors/genetics/metabolism [MESH]
  • |Janus Kinases/*antagonists & inhibitors/genetics/metabolism [MESH]
  • |Killer Cells, Natural/*immunology [MESH]
  • |Male [MESH]
  • |Mice [MESH]
  • |Mice, Nude [MESH]
  • |Primary Cell Culture [MESH]
  • |Prostatic Neoplasms, Castration-Resistant/*immunology/therapy [MESH]


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