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The effects of KIR2DL4 stimulated NK-92 cells on the apoptotic pathways of HER2 + /HER-breast cancer cells

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Abstract

Natural killer (NK) cells are immune cells that have attracted significant attention due to their cytotoxic properties. They are believed to be highly effective in cancer therapy. In this study, anti-KIR2DL4 (Killer cell Immunoglobulin like Receptor, 2 Ig Domains and Long cytoplasmic tail 4) was used to stimulate the NK-92 activator receptor to increase their cytotoxicity on breast cancer cell lines. Unstimulated and stimulated NK-92 cells (sNK-92) were cocultured with breast cancer (MCF-7 and SK-BR-3) and normal breast (MCF-12A) cell lines at 1:1, 1:5, and 1:10 (Target:Effector) ratios. The most effective cell cytotoxicity ratio (1:10) was used in the immunostaining and western blot assays to evaluate apoptosis pathway proteins. The sNK-92 cells showed higher cytotoxic activity on breast cancer cells than NK-92 cells. sNK-92 cells had a selective significant cytotoxicity effect on MCF-7 and SK-BR-3 cells but not MCF-12A cells. While sNK-92 cells were effective at all cell concentrations, they were most effective at a 1:10 ratio. Immunostaining and western blots showed significantly higher BAX, caspase 3, and caspase 9 protein levels in all breast cancer cell groups cocultured with sNK-92 than with NK-92 cells. NK-92 cells stimulated with KIR2DL4 showed elevated cytotoxic activity. The cytotoxic activity of sNK-92 cells on breast cancer cells is via apoptosis pathways. However, their effect on normal breast cells is limited. While the obtained data contains only basic information, additional clinical studies are needed to provide a basis for a new treatment model.

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Data availability

All datasets used or analyzed during the current study are available from the corresponding author on reasonable request.

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Funding

We thank Ankara University, Management of Scientific Research Projects (BAP project no. 20L0430006), for the financial support. We thank Ankara University, Management of Scientific Research Projects (BAP project no. 20L0430006), for the financial support.

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Authors and Affiliations

  1. Department of Biology, Faculty of Science, Ankara University, Tandogan Campus, 06100, Ankara, Turkey

    Nil Kilic & Irfan Kandemir

  2. Ankara University Biotechnology Institute and SISBIYOTEK Advanced Research Unit, Gumusdere Yerleskesi, Kecioren Ankara, 06135, Turkey

    Mohammadreza Dastouri & Erkan Yilmaz

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  1. Nil Kilic
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Contributions

MD and NK designed the experiments, developed the methodology analyzed results, prepared data presentations, and wrote and reviewed the draft manuscript. EY and IK analyzed results and reviewed the draft manuscript; IK was responsible for project administration and provision of study materials and equipment. MD was the project supervisor.

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Correspondence to Mohammadreza Dastouri.

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Kilic, N., Dastouri, M., Kandemir, I. et al. The effects of KIR2DL4 stimulated NK-92 cells on the apoptotic pathways of HER2 + /HER-breast cancer cells. Med Oncol 40, 139 (2023). https://doi.org/10.1007/s12032-023-02009-6

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