Raddeanin A augments the cytotoxicity of natural killer cells against chronic myeloid leukaemia cells by modulating MAPK and Ras/Raf signalling pathways

Author:

Hsieh Ming‐Ju1234ORCID,Lin Jen‐Tsun5,Chuang Yi‐Ching1,Lo Yu‐Sheng1,Lin Chia‐Chieh1ORCID,Ho Hsin‐Yu1,Chen Mu‐Kuan367

Affiliation:

1. Oral Cancer Research Center Changhua Christian Hospital Changhua Taiwan

2. Doctoral Program in Tissue Engineering and Regenerative Medicine, College of Medicine National Chung Hsing University Taichung Taiwan

3. Graduate Institute of Clinical Medicine, College of Medicine National Chung Hsing University Taichung Taiwan

4. Graduate Institute of Biomedical Sciences China Medical University Taichung Taiwan

5. Division of Hematology and Oncology, Department of Medicine Changhua Christian Hospital Changhua Taiwan

6. Department of Otorhinolaryngology, Head and Neck Surgery Changhua Christian Hospital Changhua Taiwan

7. Department of Post‐Baccalaureate Medicine, College of Medicine National Chung Hsing University Taichung Taiwan

Abstract

AbstractNatural killer (NK) cell therapy, a developing approach in cancer immunotherapy, involves isolating NK cells from peripheral blood. However, due to their limited number and activity, it is essential to significantly expand these primary NK cells and enhance their cytotoxicity. In this study, we investigated how Raddeanin A potentiate NK activity using KHYG‐1 cells. The results indicated that Raddeanin A increased the expression levels of cytolytic molecules such as perforin, granzymes A and granzymes B, granulysin and FasL in KHYG‐1 cells. Raddeanin A treatment increased CREB phosphorylation, p65 phosphorylation, NFAT1 and acetyl‐histone H3 expression. Raddeanin A elevated caspase 3 and PARP cleavage, increased t‐Bid expression, promoting apoptosis in K562 cells. Furthermore, it reduced the expression of HMGB2, SET and Ape1, impairing the DNA repair process and causing K562 cells to die caspase‐independently. Additionally, Raddeanin A increased ERK, p38 and JNK phosphorylation at the molecular level, which increased granzyme B production in KHYG‐1 cells. Raddeanin A treatment increased Ras, Raf phosphorylation, MEK phosphorylation, NKG2D, NKp44 and NKp30 expression in KHYG‐1 cells. Collectively, our data indicate that Raddeanin A enhances the cytotoxic activity of NK cells against different cancer cells.

Publisher

Wiley

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