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Exportin-1 is critical for cell proliferation and survival in adult T cell leukemia

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Abstract

Since treatment options for adult T cell leukemia (ATL) associated with human T cell leukemia virus type 1 (HTLV-1) fail to obtain long-term response, novel therapies targeting ATL-dysregulated pathways are necessary. Dysregulated nuclear import and export machinery is common in malignancies. This study aimed to investigate the potential of exportin-1 (XPO1), which mediates nuclear export of cargos, as a target in ATL. RT-PCR and western blotting were performed to determine XPO1 expression. We evaluated XPO1’s effects on cell proliferation and viability through WST-8 assays, cell cycle and apoptosis via Hoechst 33342 staining and flow cytometry, and intracellular signaling cascades using western blotting. XPO1 expression was upregulated in HTLV-1-infected T cells. XPO1 knockdown reduced cell proliferation. XPO1 inhibitor KPT-330 also reduced proliferation, increased DNA damage, and induced G1 cell cycle arrest and caspase-dependent apoptosis. KPT-330 downregulated cell cycle regulators (CDK2/4/6, cyclin D2, c-Myc and phosphorylated pRb) and anti-apoptotic proteins (XIAP, c-IAP1/2, survivin and Mcl-1), and upregulated p53, p21 and Bak. KPT-330 suppressed XPO1 and increased the nuclear localization of cargos (NF-κB RelA and its negative regulator IκBα, protein phosphatase 2A and its inhibitor SET, p53 and its negative regulator MDM2, p21, p27, FOXO1 and pRb). KPT-330 treatment resulted in the abrogation of aberrant pathways (NF-κB, Akt and STAT3/5) simultaneously through the activation of tumor suppressor proteins and inhibition of oncogenes and proliferative/survival factors. These findings encourage investigating the use of KPT-330 in clinical trials targeting ATL.

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Data availability

The data and materials used in this study are available from the corresponding author on reasonable request.

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Acknowledgements

We would like to thank Fujisaki Cell Center, Hayashibara Biochemical Laboratories, Inc. for providing HUT-102 and MT-1 cells, Dr. Naoki Yamamoto (Tokyo Medical and Dental University) for providing MT-2 and MT-4 cells, Dr. Diane Prager (UCLA School of Medicine) for providing SLB-1 cells, Dr. Masahiro Fujii (Niigata University) for providing TL-OmI cells, and Dr. Yuetsu Tanaka (University of the Ryukyus) for providing Lt-4 antibody. Recombinant human IL-2 was provided by Takeda Pharmaceutical Co. Ltd. The measurement of protein concentrations and flow cytometric analyses were performed at the University of the Ryukyus Center for Research Advancement and Collaboration. We would like to thank Editage (www.editage.jp) for their assistance with English language editing.

Funding

This study was partially supported by JSPS KAKENHI (17K07175).

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Authors and Affiliations

  1. Department of Microbiology and Oncology, Graduate School of Medicine, University of the Ryukyus, 207 Uehara, Nishihara, Okinawa, 903-0215, Japan

    Naoki Mori & Naoki Mori

  2. Division of Health Sciences, Transdisciplinary Research Organization for Subtropics and Island Studies, University of the Ryukyus, 1 Senbaru, Nishihara, Okinawa, 903-0213, Japan

    Naoki Mori

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  1. Chie Ishikawa
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Conceptualization: N.M.; methodology: C.I. and N.M.; formal analysis and investigation: C.I. and N.M.; writing-original draft preparation: C.I.; writing-reviewing and editing: N.M.; funding acquisition: C.I.; resources: N.M.; supervision: N.M.

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Correspondence to Naoki Mori.

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Ishikawa, C., Mori, N. Exportin-1 is critical for cell proliferation and survival in adult T cell leukemia. Invest New Drugs 40, 718–727 (2022). https://doi.org/10.1007/s10637-022-01250-6

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