Bruton's agammaglobulinemia tyrosine kinase (Btk) regulates TPA‑induced breast cancer cell invasion via PLCγ2/PKCβ/NF‑κB/AP‑1‑dependent matrix metalloproteinase‑9 activation

Kim,Jeong-Mi; Park,Jinny; Noh,Eun-Mi; Song,Hyun-Kyung; Kang,Sang Yull; Jung,Sung Hoo; Kim,Jong-Suk; Park,Byung-Hyun; Lee,Young-Rae; Youn,Hyun Jo

doi:10.3892/or.2021.8007

Bruton's agammaglobulinemia tyrosine kinase (Btk) regulates TPA‑induced breast cancer cell invasion via PLCγ2/PKCβ/NF‑κB/AP‑1‑dependent matrix metalloproteinase‑9 activation

Authors:
- Jeong-Mi Kim
- Jinny Park
- Eun-Mi Noh
- Hyun-Kyung Song
- Sang Yull Kang
- Sung Hoo Jung
- Jong-Suk Kim
- Byung-Hyun Park
- Young-Rae Lee
- Hyun Jo Youn
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Affiliations: Department of Biochemistry, Institute of Medical Science, Chonbuk National University Medical School, Jeonju, Jeollabuk 560‑182, Republic of Korea, Department of Internal Medicine, Division of Hematology, Gil Medical Center, Gachon University College of Medicine, Incheon 405‑760, Republic of Korea, Department of Oral Biochemistry, School of Dentistry, Wonkwang University, Iksan, Jeollabuk 570‑749, Republic of Korea, Department of Surgery, Research Institute of Clinical Medicine, Jeonbuk National University Hospital, Jeonbuk National University and Biomedical Research Institute, Jeonju, Jeollabuk 560‑182, Republic of Korea, Department of Biochemistry and Molecular Biology and Director of Center for Meta Inflammation Research, Chonbuk National University Medical School, Jeonju, Jeonbuk 54896, Republic of Korea
Published online on: March 9, 2021 https://doi.org/10.3892/or.2021.8007
Article Number: 56
Copyright: © Kim et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Bruton's agammaglobulinemia tyrosine kinase (BTK) is an important cytoplasmic tyrosine kinase involved in B‑lymphocyte development, differentiation, and signaling. Activated protein kinase C (PKC), in turn, induces the activation of mitogen‑activated protein kinase (MAPK) signaling, which promotes cell proliferation, viability, apoptosis, and metastasis. This effect is associated with nuclear factor‑κB (NF‑κB) activation, suggesting an anti‑metastatic effect of BTK inhibitors on MCF‑7 cells that leads to the downregulation of matrix metalloproteinase (MMP)‑9 expression. However, the effect of BTK on breast cancer metastasis is unknown. In this study, the anti‑metastatic activity of BTK inhibitors was examined in MCF‑7 cells focusing on MMP‑9 expression in 12‑O‑tetradecanoylphorbol‑13‑acetate (TPA)‑stimulated MCF‑7 cells. The expression and activity of MMP‑9 in MCF‑7 cells were investigated using quantitative polymerase chain reaction analysis, western blotting, and zymography. Cell invasion and migration were investigated using the Matrigel invasion and cell migration assays. BTK inhibitors [ibrutinib (10 µM), CNX‑774 (10 µM)] significantly attenuated TPA‑induced cell invasion and migration in MCF‑7 cells and inhibited the activation of the phospholipase Cγ2/PKCβ signaling pathways. In addition, small interfering RNA specific for BTK suppressed MMP‑9 expression and cell metastasis. Collectively, results of the present study indicated that BTK suppressed TPA‑induced MMP‑9 expression and cell invasion/migration by activating the MAPK or IκB kinase/NF‑κB/activator protein‑1 pathway. The results clarify the mechanism of action of BTK in cancer cell metastasis by regulating MMP‑9 expression in MCF‑7 cells.

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