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Current Affiliation Organization 【 display / non-display 】

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Published Papers 【 display / non-display 】

Published Papers 【 display / non-display 】

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

  Ishikawa C, Mori N

  Investigational new drugs ( Investigational New Drugs )  40 ( 4 ) 718 - 727   2022.08 [ Peer Review Accepted ]

  Type of publication: Research paper (scientific journal)

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• FX1, a BCL6 inhibitor, reactivates BCL6 target genes and suppresses HTLV-1-infected T cells.

  Ishikawa C, Mori N

  Investigational new drugs ( Investigational New Drugs )  40 ( 2 ) 245 - 254   2022.04 [ Peer Review Accepted ]

  Type of publication: Research paper (scientific journal)

  　View Summary

  Human T cell leukemia virus type 1 (HTLV-1) is responsible for adult T cell leukemia (ATL); however, molecular and cellular mechanisms underlying HTLV-1-induced leukemogenesis are unclear. BCL6 oncogene is involved in cancer progression and a preferred target of anti-cancer treatments. Here, we aimed to evaluate BCL6 expression and the effects of BCL6 inhibitor (FX1) on HTLV-1-infected T cell lines. BCL6 expression was higher in HTLV-1-infected T cell lines than that in uninfected T cell lines. BCL6 was localized mostly in the nucleus. The virus oncoprotein Tax induced BCL6 mRNA expression in T cells, whereas BCL6 knockdown reduced HTLV-1-infected T cell proliferation; thus, confirmed the association of BCL6 with cancer progression. Further, FX1 efficiently inhibited the cell growth and survival of HTLV-1-infected T cell lines in a dose- and time-dependent manner. The decreased levels of cell cycle regulatory proteins (phosphorylated retinoblastoma protein, cyclin-dependent kinase 4, cyclin D2 and c-Myc) and the increased levels of BCL6 target proteins (p21, p27 and p53) showed that FX1 arrested cell cycle at the G1 phase. Apoptosis was induced concomitantly with Bak upregulation and downregulation of survivin, Bcl-xL and Mcl-1, as well as with the activation of caspase-3, -8, -9 and poly(ADP-ribose) polymerase. FX1 also inhibited NF-κB and Akt signaling pathways. These events were because of the induction of the activity of cell cycle checkpoint proteins and relief of direct repression of the targets of cell cycle checkpoint proteins. Thus, BCL6 might be considered a novel target for ATL treatment.

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• The antipsychotic drug pimozide is effective against human T-cell leukemia virus type 1-infected T cells.

  Ishikawa C, Mori N

  European journal of pharmacology ( European Journal of Pharmacology )  908   174373 - 174373   2021.10 [ Peer Review Accepted ]

  Type of publication: Research paper (scientific journal)

  　View Summary

  Patients with adult T-cell leukemia (ATL), caused by the human T-cell leukemia virus type 1 (HTLV-1), exhibit poor prognosis owing to drug resistance. Pimozide is a dopamine D2 receptor antagonist and antipsychotic shown to exhibit anticancer activity. Herein, we investigated whether pimozide exerts anti-ATL effects and explored the mechanisms underlying these effects. Pimozide inhibited cell growth and survival in HTLV-1-infected T cells but not in the uninfected T cells. The dopamine D2 receptor subfamily mRNA expression levels in HTLV-1-infected T cells were high. Pimozide induced G1 cell cycle arrest concomitant with the upregulation of p21/p27/p53, and suppression of cyclin D2/E, cyclin-dependent kinase 2/4/6 and c-Myc expression, and pRb phosphorylation. Pimozide also induced apoptosis by activating caspases, upregulating pro-apoptotic proteins and downregulating anti-apoptotic proteins. Additionally, it promoted reactive oxygen species (ROS) generation and increased the expression of the endoplasmic reticulum stress marker activating transcription factor 4 and the DNA damage-inducible protein GADD45α and the phosphorylation of the DNA damage marker H2AX. Furthermore, pimozide-induced cytotoxicity was partially inhibited by a ROS scavenger, and pan-caspase and necroptosis inhibitors, indicating the involvement of caspase-dependent and -independent lethal pathways. The activities of the nuclear factor-κB, Akt, STAT3/5 and AP-1 signaling pathways were inhibited via the dephosphorylation of IκBα, IκB kinase α/β, Akt and STAT3/5, in addition to reduced JunB and JunD expression in HTLV-1-infected T cells. Pimozide also exhibited potent anti-ATL activity in the xenograft mouse model. These findings demonstrated the efficacy of pimozide as a potential therapeutic agent for ATL.

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• Importin β1 regulates cell growth and survival during adult T cell leukemia/lymphoma therapy.

  Ishikawa C, Senba M, Mori N

  Investigational new drugs ( Investigational New Drugs )  39 ( 2 ) 317 - 329   2020.09 [ Peer Review Accepted ]

  Type of publication: Research paper (scientific journal)

  　View Summary

  There is no cure for adult T cell leukemia/lymphoma (ATLL) associated with human T cell leukemia virus type 1 (HTLV-1), and novel targeted strategies are needed. NF-κB and AP-1 are crucial for ATLL, and both are transported to the nucleus by an importin (IPO)α/β heterodimeric complex to activate target genes. In this study, we aimed to elucidate the function of IPOβ1 in ATLL. The expression of IPOβ1 was analyzed by western blotting and RT-PCR. Cell growth, viability, cell cycle, apoptosis and intracellular signaling cascades were examined by the water-soluble tetrazolium-8 assay, flow cytometry and western blotting. Xenograft tumors in severe combined immune deficient mice were used to evaluate the growth of ATLL cells in vivo. IPOβ1 was upregulated in HTLV-1-infected T cell lines. Further, IPOβ1 knockdown or the IPOβ1 inhibitor importazole and the IPOα/β1 inhibitor ivermectin reduced HTLV-1-infected T cell proliferation. However, the effect of inhibitors on uninfected T cells was less pronounced. Further, in HTLV-1-infected T cell lines, inhibitors suppressed NF-κB and AP-1 nuclear transport and DNA binding, induced apoptosis and poly (ADP-ribose) polymerase cleavage, and activated caspase-3, caspase-8 and caspase-9. Inhibitors also mediated G1 cell cycle arrest. Moreover, the expression of NF-κB- and AP-1-target proteins involved in cell cycle and apoptosis was reduced. In vivo, the IPOα/β1 inhibitor ivermectin decreased ATLL tumor burden without side effects. IPOβ1 mediated NF-κB and AP-1 translocation into ATLL cell nuclei, thereby regulating cell growth and survival, which provides new insights for targeted ATLL therapies. Thus, ivermectin, an anti-strongyloidiasis medication, could be a potent anti-ATLL agent.

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• The anti-malaria agent artesunate exhibits cytotoxic effects in primary effusion lymphoma.

  Ishikawa C, Mori N

  Investigational new drugs ( Investigational New Drugs )    2020.09 [ Peer Review Accepted ]

  Type of publication: Research paper (scientific journal)

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Books 【 display / non-display 】

Books 【 display / non-display 】

• Mechanisms of cancer formation under interplay between host immunity and human papillomavirus (HPV) infection

  Senba M, Mori N ( Part: Multiple Authorship )

  Nova Science Publishers  2016

• Challenge to the threat of invisible transmission: global health security for the control of emerging infectious diseases outbreaks

  Senba M, Mori N ( Part: Multiple Authorship )

  Nova Science Publishers  2016

• Mechanisms of cancer formation under interplay between host immunity and human papillomavirus (HPV) infection

  Senba M, Mori N ( Part: Single Author )

  Nova Science Publishers  2016

• Challenge to the threat of invisible transmission: global health security for the control of emerging infectious diseases outbreaks

  ( Part: Single Author )

  2016

• Challenge to the threat of invisible transmission: Global health security for the control of emerging infectious disease outbreaks

  Senba M, Mori N ( Part: Single Author )

  Nova Science Publishers  2016

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Other Papers 【 display / non-display 】

Other Papers 【 display / non-display 】

• MALT1 as a novel therapeutic target for adult T-cell leukemia

      S161   2019.10

   

• 新規PI3K/HDAC二重阻害剤CUDC-907は原発性体腔液性リンパ腫の複数の細胞生存シグナルを抑制する

  森直樹, 石川千恵

  第78回日本癌学会学術総会プログラム集     187   2019.09

   

• Evaluation of artesunate for the treatment of adult T‐cell leukemia

  Naoki Mori, Chie Ishikawa

  臨床血液   59 ( 9 ) 1720 - 1720   2018.09

   

  J-GLOBAL

• アルテスネイトの原発性体腔液性リンパ腫に対する治療効果

  石川千恵, 森直樹

  第77回日本癌学会学術総会プログラム集 ( 日本癌学会 )    124   2018.09

   

  J-GLOBAL

• ATL治療薬としての新規PI3K/HDAC二重阻害剤CUDC-907

  森直樹, 石川千恵

  第77回日本癌学会学術総会プログラム集 ( 日本癌学会 )    71   2018.09

   

  J-GLOBAL

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Grant-in-Aid for Scientific Research 【 display / non-display 】

Grant-in-Aid for Scientific Research 【 display / non-display 】

• Grant-in-Aid for Scientific Research(C)

  Project Year: 2013.04  -  2016.03 

  Direct: 3,900,000 (YEN)  Overheads: 1,170,000 (YEN)  Total: 5,070,000 (YEN)

• Grant-in-Aid for Scientific Research(C)

  Project Year: 2009.04  -  2011.03 

  Direct: 2,600,000 (YEN)  Overheads: 780,000 (YEN)  Total: 3,380,000 (YEN)

• Grant-in-Aid for Scientific Research on Priority Areas

  Project Year: 2008.04  -  2010.03 

  Direct: 10,600,000 (YEN)  Overheads: 3,180,000 (YEN)  Total: 13,780,000 (YEN)

• Grant-in-Aid for Scientific Research(C)

  Project Year: 2007.04  -  2009.03 

  Direct: 3,500,000 (YEN)  Overheads: 1,050,000 (YEN)  Total: 4,550,000 (YEN)

• Grant-in-Aid for Scientific Research(C)

  Project Year: 2004.04  -  2006.03 

  Direct: 3,600,000 (YEN)  Overheads: 1,080,000 (YEN)  Total: 4,680,000 (YEN)

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