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Mitogen-activated protein kinases are involved in cucurbitacin D-induced antitumor effects on adult T-cell leukemia cells

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Summary

Adult T cell leukemia (ATL) is an aggressive and malignant blood disease. We previously reported that steroid-structured cucurbitacin D (CuD) induces apoptosis in ATL cells. In this study, we investigated the effects of mitogen-activated protein kinase (MAPK) signaling inhibitors on CuD-induced cell death in peripheral blood lymphocytes (PBLs) isolated from ATL/acute lymphoblastic leukemia (ALL) patients and two human leukemia cell lines (MT-1 and MT-4). PBLs were isolated from an ATL/ALL patient as well as from a healthy donor. Cell surface markers were examined using flow cytometry. Serum cytokine levels were estimated using LEGENDplex or analyzed at the Center for Clinical and Translational Research of Kyushu University Hospital. Cell proliferation was assessed using the Cell Titer-Glo luminescent cell viability assay. Protein expression was determined by western blotting. PBLs from patients highly expressed CD4 and CD5. Serum from the patient contained high levels of interleukin (IL)-8, IL-10, IL-18, and interferon-γ compared to the healthy donor. CuD-induced cell death was enhanced by the mitogen-activated protein kinase kinase (MEK)1/2 inhibitor U0126. However, a c-Jun N-terminal kinase (JNK) inhibitor prevented CuD-induced cell death. Immunoblot analyses revealed that CuD reduced the phosphorylation of extracellular signal-regulated kinase (ERK), p38, and JNK, and co-treatment with CuD and U0126 did not affect the phosphorylation of ERK. MEK1/2 and p38 inhibitors enhanced CuD-induced cell death, and U0126 enhanced the CuD-induced de-phosphorylation of ERK in MT-1 and MT-4 cells. We conclude that CuD reduces ERK activation, resulting in enhanced antitumor effects on leukemic cells.

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Abbreviations

ATL:

Adult T-cell leukemia

CuD:

Cucurbitacin D

MAPK:

Mitogen-activated protein kinase

PBLs:

Peripheral blood lymphocytes

IL:

Interleukin

MEK:

Mitogen-activated protein kinase kinase

JNK:

c-Jun N-terminal kinase

ERK:

Extracellular signal-regulated kinase

IFN:

Interferon

TNF:

Tumor necrosis factor

MCP:

Monocyte chemoattractant protein

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Acknowledgments

Analysis of cytokine production was partially supported by the Center for Clinical and Translational Research of the Kyushu University Hospital, Japan.

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

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Authors and Affiliations

  1. Department of Immunology and Parasitology, School of Medicine, University of Occupational and Environmental Health, 1-1 Iseigaoka, Yahatanishi-ku, Kitakyushu, 807-8555, Japan

    Duo Wang, Mengyue Shen, Yusuke Sennari, Kentaro Morita, Tamotsu Kanazawa & Yasuhiro Yoshida

  2. Department of Hematology, School of Medicine, University of Occupational and Environmental Health, 1-1 Iseigaoka, Yahatanishi-ku, Kitakyushu, 807-8555, Japan

    Noriaki Kitamura & Junichi Tsukada

Authors
  1. Duo Wang
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  2. Mengyue Shen
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  3. Noriaki Kitamura
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  7. Tamotsu Kanazawa
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  8. Yasuhiro Yoshida
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Contributions

DW, NK, JT, and YY designed the clinical study and DW wrote the manuscript. DW, KM, and MS performed data collection and analysis. TK approved the clinical study and YY approved the manuscript. All authors have read and approved the final manuscript.

Corresponding author

Correspondence to Yasuhiro Yoshida.

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Conflict of interest

The authors declare that they have no competing interests.

Ethics approval

This study was approved by the University of Occupational and Environmental Health, Japan (approval no. H26–034). All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

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All patients provided written consent to participate in the study.

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All participants provided written consent to participate and publish the data.

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Key points

• CuD-induced cell death was enhanced by the MEK1/2 inhibitor U0126.

• CuD can reduce ERK activation, resulting in enhanced antitumor effects in ATL cells.

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Wang, D., Shen, M., Kitamura, N. et al. Mitogen-activated protein kinases are involved in cucurbitacin D-induced antitumor effects on adult T-cell leukemia cells. Invest New Drugs 39, 122–130 (2021). https://doi.org/10.1007/s10637-020-00997-0

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  • DOI: https://doi.org/10.1007/s10637-020-00997-0

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