ICHIKAWA Tomonaga

写真a

Affiliation

Faculty of Medicine School of Medicine Department of Medical Sciences, Vascular and cellular dynamics

Title

Assistant Professor

External Link

Degree 【 display / non-display

  • 博士(医学) ( 2005.3   筑波大学 )

Research Areas 【 display / non-display

  • Life Science / Medical biochemistry

 

Papers 【 display / non-display

  • Role of Mel1/Prdm16 in bone differentiation and morphology.

    Kaneda-Nakashima K, Igawa K, Suwanruengsri M, Naoyuki F, Ichikawa T, Funamoto T, Kurogi S, Sekimoto T, Yamashita Y, Chosa E, Yamaguchi R, Morishita K

    Experimental cell research   112969   2021.12

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    Language:English   Publishing type:Research paper (scientific journal)  

    DOI: 10.1016/j.yexcr.2021.112969

    PubMed

  • Antitumor effects of chloroquine/ hydroxychloroquine mediated by inhibition of the NF-κB signaling pathway through abrogation of autophagic p47 degradation in adult T-cell leukemia/lymphoma cells

    Fauzi Y.R., Nakahata S., Chilmi S., Ichikawa T., Nueangphuet P., Yamaguchi R., Nakamura T., Shimoda K., Morishita K.

    PLoS ONE   16 ( 8 August )   e0256320   2021.8

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    Language:Japanese   Publishing type:Research paper (scientific journal)   Publisher:PLoS ONE  

    Adult T-cell leukemia/lymphoma (ATLL) originates from human T-cell leukemia virus type 1 (HTLV-1) infection due to the activation of the nuclear factor-κB (NF-κB) signaling pathway to maintain proliferation and survival. An important mechanism of the activated NF-κB signaling pathway in ATLL is the activation of the macroautophagy (herafter referred to as autophagy in the remainder of this manuscript)-lysosomal degradation of p47 (NSFL1C), a negative regulator of the NF-κB pathway. Therefore, we considered the use of chloroquine (CQ) or hydroxychloroquine (HCQ) (CQ/HCQ) as an autophagy inhibitor to treat ATLL; these drugs were originally approved by the FDA as antimalarial drugs and have recently been used to treat autoimmune diseases, such as systemic lupus erythematosus (SLE). In this paper, we determined the therapeutic efficacy of CQ/HCQ, as NF-κB inhibitors, in ATLL mediated by blockade of p47 degradation. Administration of CQ/HCQ to ATLL cell lines and primary ATLL cells induced cell growth inhibition in a dose-dependent manner, and the majority of cells underwent apoptosis after CQ administration. As to the molecular mechanism, autophagy was inhibited in CQ-treated ATLL cells, and activation of the NF-κB pathway was suppressed with the restoration of the p47 level. When the antitumor effect of CQ/ HCQ was examined using immunodeficient mice transplanted with ATLL cell lines, CQ/ HCQ significantly suppressed tumor growth and improved the survival rate in the ATLL xenograft mouse model. Importantly, HCQ selectively induced ATLL cell death in the ATLL xenograft mouse model at the dose used to treat SLE. Taken together, our results suggest that the inhibition of autophagy by CQ/HCQ may become a novel and effective strategy for the treatment of ATLL.

    DOI: 10.1371/journal.pone.0256320

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  • Pathophysiological significance of N-myc downstream-regulated gene 2 in cancer development through protein phosphatase 2A phosphorylation regulation

    Morishita K., Nakahata S., Ichikawa T.

    Cancer Science   112 ( 1 )   22 - 30   2021.1

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    Language:Japanese   Publishing type:Research paper (scientific journal)   Publisher:Cancer Science  

    N-myc downstream-regulated gene 2 (NDRG2) is a candidate tumor suppressor in various cancers, including adult T-cell leukemia/lymphoma (ATLL). NDRG2, as a stress-responsive protein, is induced by several stress-related signaling pathways and NDRG2 negatively regulates various signal transduction pathways. Although it has not been found to function alone, NDRG2 binds serine/threonine protein phosphatase 2A (PP2A), generating a complex that is involved in the regulation of various target proteins. The main function of NDRG2 is to maintain cell homeostasis by suppressing stress-induced signal transduction; however, in cancer, genomic deletions and/or promoter methylation may inhibit the expression of NDRG2, resulting in enhanced tumor development through overactivated signal transduction pathways. A wide variety of tumors develop in Ndrg2-deficient mice, including T-cell lymphoma, liver, lung and other tumors, the characteristics of which are similar to those in Pten-deficient mice. In particular, PTEN is a target molecule of the NDRG2/PP2A complex, which enhances PTEN phosphatase activity by dephosphorylating residues in the PTEN C-terminal region. In ATLL cells, loss of NDRG2 expression leads to the failed recruitment of PP2A to PTEN, resulting in the inactivation of PTEN phosphatase with phosphorylation, ultimately leading to the activation of PI3K/AKT. Thus, NDRG2, as a PP2A adaptor, regulates the global phosphorylation of important signaling molecules. Moreover, the downregulation of NDRG2 expression by long-term stress-induced methylation is directly correlated with the development of ATLL and other cancers. Thus, NDRG2 might be important for the development of stress-induced leukemia and other cancers and has become an important target for novel molecular therapies.

    DOI: 10.1111/cas.14716

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  • Development of anti-human CADM1 monoclonal antibodies as a potential therapy for adult T-cell leukemia/lymphoma. Reviewed

    Chilmi S, Nakahata S, Fauzi YR, Ichikawa T, Tani C, Suwanruengsri M, Yamaguchi R, Matsuura T, Kurosawa G, Morishita K.

    Int J Hematol   112 ( 4 )   496 - 503   2020.7

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    Language:English   Publishing type:Research paper (scientific journal)   Publisher:International Journal of Hematology  

    Adult T-cell leukemia/lymphoma (ATLL) is a highly invasive and refractory T-cell malignancy, with poor prognosis. We previously identified that cell adhesion molecule 1 (CADM1) is overexpressed consistently in ATLL cells, and that CADM1 expression increases the adhesion capacity of ATLL cells to endothelial cells and promotes the organ invasion of ATLL cells in a xenograft mouse model. In this study, we first show that newly developed several anti-human CADM1 antibodies, which were complete human IgG antibodies generated by phage display method, specifically recognize CADM1 on ATLL cells. Although most of the CADM1 antibodies did not have a direct cytotoxic effect against CADM1-positive ATLL cells, clone 089–084 exhibited weak but significant antibody-dependent cell-mediated cytotoxic activity. Moreover, clone 103–189 effectively inhibits the interaction between endothelial cells and CADM1-positive ATLL cells. Furthermore, in mice bearing intra-splenic transplantation of EL4 mouse lymphoma cells expressing CADM1, the treatment of 103–189 significantly suppressed the organ invasion of CADM1-positive EL4 cells, resulting in improved survival time of mice. Therefore, since the anti-CADM1 antibody may be useful for the suppression of organ invasion in ATLL patients, combination use of the anti-CADM1 antibody with chemotherapy drugs could be beneficial for the efficient elimination of ATLL cells.

    DOI: 10.1007/s12185-020-02939-1

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  • Novel PRMT5-mediated arginine methylations of HSP90A are essential for maintenance of HSP90A function in NDRG2low ATL and various cancer cells. Reviewed

    Ichikawa T., Shanab O., Nakahata S., Shimosaki S., Manachai N., Ono M., Iha H., Shimoda K., Morishita K.

    Biochimica et Biophysica Acta - Molecular Cell Research   1867 ( 2 )   118615   2020.2

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    Language:English   Publishing type:Research paper (scientific journal)   Publisher:Biochimica et Biophysica Acta - Molecular Cell Research  

    N-myc downstream-regulated gene 2 (NDRG2) as a tumor suppressor is frequently downregulated in human T-lymphotropic retrovirus (HTLV-1)-infected adult T-cell leukemia (ATL) and variety of cancers, and negatively regulates PI3K signaling pathways through dephosphorylation of PTEN with protein phosphatase 2A (PP2A). We recently identified that protein arginine methyltransferase 5 (PRMT5) is one of novel NDRG2 binding proteins and the knockdown of PRMT5 induces cell apoptosis with degradation of several signaling molecules. To investigate how the apoptosis is induced by the knockdown PRMT5 expression, heat shock protein 90 alpha (HSP90A) was identified as a binding protein for NDRG2 or PRMT5 by immunoprecipitation-mass analysis. NDRG2/PP2A complex inhibited arginine methyltransferase activity of PRMT5 through dephosphorylation at Serine 335 (S335); however, in NDRG2low ATL-related cells, highly phosphorylated PRMT5 at S335 was mainly localized in cytoplasm with binding to HSP90A, resulting in enhancing arginine-methylation at the middle domain (R345 and R386). Since knockdown of PRMT5 expression or forced expression of HSP90A with alanine replacement of R345 or R386 induced apoptosis with the degradation of client proteins in NDRG2low ATL-related and other cancer cells, we here identified that the novel arginine methylations of HSP90A are essential for maintenance of its function in NDRG2low ATL and other cancer cells.

    DOI: 10.1016/j.bbamcr.2019.118615

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MISC 【 display / non-display

  • HSP90アルギニンメチル化による発がん機構の解明

    市川朝永

    Medical Science Digest   2021

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    Authorship:Lead author   Publishing type:Rapid communication, short report, research note, etc. (scientific journal)  

  • 高リン酸化型PRMT5によるHSP90アルギニンメチル化はがん発症進展に寄与する

    市川朝永

    月刊「細胞」   2021

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    Authorship:Lead author   Publishing type:Rapid communication, short report, research note, etc. (scientific journal)  

  • Corrigendum to “Development of a complete human IgG monoclonal antibody to transferrin receptor 1 targeted for adult T-cell leukemia/lymphomaˮ [Biochem. Biophys. Res. Commun. 485 (1) 2017 144–151] (Biochemical and Biophysical Research Communications (2017) 485(1) (144–151), (S0006291X17303078), (10.1016/j.bbrc.2017.02.039))

    Shimosaki S., Nakahata S., Ichikawa T., Kitanaka A., Kameda T., Hidaka T., Kubuki Y., Kurosawa G., Zhang L., Sudo Y., Shimoda K., Morishita K.

    Biochemical and Biophysical Research Communications   530 ( 2 )   486   2020.9

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    Language:Japanese   Publishing type:Rapid communication, short report, research note, etc. (scientific journal)   Publisher:Biochemical and Biophysical Research Communications  

    The authors regret that the day of antibody injection for NOG mice subcutaneously transplanted with MT-2 or HH must be corrected from “every 3 days” to “every 3–4 days” in the part of “Supplementary materials and methods”. The authors also regret that the day of antibody injection for NOG mice subcutaneously transplanted with MT-2 or Su9T01 must be corrected from “two times per week for 2 weeks” to “on day 1, day 8, day 15, and day 21 post-cell injection” in the part of “Supplementary materials and methods”. These corrections do not change the conclusions of this manuscript. The authors would like to apologise for any inconvenience caused. The correct supplementary materials and methods. In vivo experimental therapy studies. Six-to eight-week-old female NOD/Shi-scid/IL-2Rγnull (NOG) or SCID mice (CLEA Japan) were given a single subcutaneous injection of 2 × 106 MT-2 cells or HH cells suspended in 100 μL PBS-diluted matrigel (BD Biosciences). When the average tumor size reached an approximate volume of 100–150 mm3, the mice were intravenously injected with either PBS, mogamulizumab, or the JST-TFR09 antibody at doses of 10 mg/kg (MT-2) or 20 mg/kg (HH) body weight 4–5 times every 3–4 days. The length and width of each tumor were measured with a caliper twice per week and used to calculate the tumor volume (length × width2/2). For Kaplan-Meier survival analysis of mice, NOG mice were given a single intravenous injection of 1 × 106 MT-2 or Su9T01 cells suspended in 100 μL PBS. At 3 days after inoculation of ATLL cells, the mice were intravenously injected with either PBS or JST-TFR09 on day 1, day 8, day 15, and day 21 post-cell injection. The survival rate of mice was observed for a period of 100 days. The authors would like to apologise for any inconvenience caused.

    DOI: 10.1016/j.bbrc.2020.05.147

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Presentations 【 display / non-display

  • Development of the treatment for adult T cell leukemia/lymphoma (ATL) by highly polymerized proanthocyanidins from blueberry leaves

    Tomonaga Ichikawa

    第94回日本生化学会  2021.11.3 

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    Event date: 2021.11.3 - 2021.11.5

    Language:Japanese   Presentation type:Poster presentation  

  • Treatment of ATL via proteasomal degradation of JAK by highly polymerized proanthocyanidins from blueberry leaves

    Tomonaga Ichikawa

    第80回日本癌学会  2021.9.30 

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    Event date: 2021.9.30 - 2021.10.2

    Language:Japanese   Presentation type:Oral presentation (general)  

  • Novel tumor suppressor gene NDRG2 deficiency promotes metabolic disorders and liver cancer development

    Tomonaga Ichikawa

    第79回日本癌学会  2020.10.1 

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    Event date: 2020.10.1 - 2020.10.3

    Language:English   Presentation type:Oral presentation (general)  

  • The activation of protein arginine methyltransferase PRMT5 promotes tumor development through Arginine methylation of HSP90A

    Tomonaga Ichikawa

    第93回日本生化学会  2020.9.14 

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    Event date: 2020.9.14 - 2020.9.16

    Language:Japanese   Presentation type:Poster presentation  

  • PRMT5 inhibition is synthetic lethal with loss of NDRG2 through the suppression of HSP90A in ATL

    Tomonaga Ichikawa

    第81回日本血液学会  2019.10.11 

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    Event date: 2019.10.11 - 2019.10.13

    Language:Japanese   Presentation type:Oral presentation (general)  

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Awards 【 display / non-display

  • 2017年度(第36回)日本癌学会奨励賞

    2017.9   日本癌学会   新規がん抑制遺伝子NDRG2によるがん進展および転移の分子機構の解明

    市川朝永

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    Award type:International academic award (Japan or overseas)  Country:Japan

  • 第2回日本HTLV1学会 Young Investigator Award (YIA)

    2015.8   日本HTLV1学会  

    市川朝永

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    Award type:Award from Japanese society, conference, symposium, etc.  Country:Japan

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

  • アルギニンメチル基転移酵素PRMT5の異常活性による発がん機構の解明

    2018 - 2021.03

    科学研究費補助金  基盤研究(C)

  • 新規PTENリン酸化酵素SCYL2の機能解析

    2015.04 - 2018.03

    科学研究費補助金  基盤研究(C)

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    Authorship:Principal investigator 

    がん抑制遺伝子PTENの不活性化は、多くの腫瘍でPI3K/AKT情報伝達系の異常亢進を引き起こし、がんの発症・進展に関与している。その原因として、ゲノム(点突然変異、欠失)やエピジェネティック(DNAメチル化)異常による発現低下と共に、近年リン酸化修飾による不活性化機構が言われてきたがその分子機構は不明であった。これまでの研究でPTEN脱リン酸化機構としてがん抑制遺伝子NDRG2の同定および機能解析を行ってきた。今回、我々はPTENリン酸化酵素(キナーゼ)の候補を同定し、さらに機能解析を行うことで、PTENによるPI3K/AKT情報伝達系の制御機構を明らかにし、PTENリン酸化酵素を標的とした新規診断治療法の開発につなげられると考えている。