Simizu, Siro

写真a

Affiliation

Faculty of Science and Technology, Department of Applied Chemistry (Yagami)

Position

Professor

Related Websites

External Links
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Profile Summary 【 Display / hide 】

  • My research interests are glycoscience, cancer cell biology and chemical biology.

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Academic Background 【 Display / hide 】

  • 1993.03

    Keio University, Faculty of Science and Engineering, Department of Applied Chemistry

    University, Graduated

  • 1998.03

    Keio University, Graduate School, Division of Science and Engineering

    Graduate School, Completed, Doctoral course

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Academic Degrees 【 Display / hide 】

  • Ph.D., Keio University, Coursework, 1998.03

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Research Areas 【 Display / hide 】

  • Nanotechnology/Materials / Bio chemistry

  • Life Science / Molecular biology

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Research Keywords 【 Display / hide 】

  • Cancer cell biology

  • Chemical Biology

  • Glycoscience

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Books 【 Display / hide 】

  • 実験医学

    宮崎 功、奥村 英夫、清水 史郎、長田 裕之, 2011

    Scope: 79-83

  • 化学と工業

    叶 直樹、清水 史郎, 2011

    Scope: 37-39

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Papers 【 Display / hide 】

  • Elucidation of structure-activity relationship of humulanolides and identification of humulanolide analog as a novel HSP90 inhibitor

    Saegusa J., Osada Y., Miura K., Sasazawa Y., Ogura A., Takao K.i., Simizu S.

    Bioorganic and Medicinal Chemistry Letters (Bioorganic and Medicinal Chemistry Letters)  60 2022.03

    ISSN  0960894X

    　View Summary

    Humulanolides are natural products isolated from Asteriscus, and the isolation and total synthesis of many types of humulanolides have been reported. In this study, we evaluated anti-proliferative activity of twelve humulanolides against various human cancer cell lines and found that humulanolide analog E, which was newly designed and synthesized, exhibited the highest anti-proliferative activity. Structure-activity relationship analysis revealed that α,β-unsaturated carbonyl moieties in humulanolides play an important role for anti-proliferative activity. To identify molecular targets of humulanolide analog E, we investigated various cell-based and in vitro assays. Treatment with humulanolide analog E against human fibrosarcoma HT1080 cells increased the expression level of HSP70 protein and decreased the levels of AKT and CDK4, which are HSP90 client proteins. Moreover, humulanolide analog E inhibited refolding of denatured luciferase protein via suppression of HSP90 activity in vitro. These results suggest that humulanolide analog E possesses the anti-proliferative activity against human cancer cells by inhibiting HSP90 functions.

  • Scalable Syntheses and Biological Evaluation of Africane-Type Sesquiterpenoids

    Matsuda Y., Koyama T., Kawano S., Miura K., Simizu S., Saikawa Y., Nakata M.

    Chemistry and Biodiversity (Chemistry and Biodiversity)  19 ( 3 )  2022.03

    ISSN  16121872

    　View Summary

    Practical total syntheses of africane-type sesquiterpenoids were realized by reexamination of a divergent strategy employing optimized three-component coupling followed by ring-closing metathesis and substrate-controlled cyclopropanation. This sequential eight-step conversion provided Δ9(15)-africanene, a common bicyclo[5.3.0]decane intermediate for the syntheses of africane derivatives, in more than twice the yield as in the previous approach. The scalability and robustness of this improved synthetic route were confirmed by gram-scale preparation of Δ9(15)-africanene. In vitro cell-based assays of the synthesized africane-type sesquiterpenoids disclosed that ester-incorporating derivatives showed cytotoxic activity against HeLa cells. The effect of relative and absolute configuration of africane-9,15-diol monoacetates on the cytotoxicity against HeLa cells was also investigated.

  • ErbB4-mediated regulation of vasculogenic mimicry capability in breast cancer cells

    Kawahara R., Simizu S.

    Cancer Science (Cancer Science)  113 ( 3 ) 950 - 959 2022.03

    ISSN  13479032

    　View Summary

    ErbB4 is a member of the ErbB receptor tyrosine kinase family. It has both pro- and anti-oncogenic activities in tumors. Vasculogenic mimicry (VM), a phenomenon in which cancer cells form capillary-like structures without endothelial cells, has been recognized to be a cause of malignant phenotypes in some solid tumors. Here, we used an in vitro VM formation assay, and demonstrated that ErbB4 negatively regulated VM formation in human breast cancer cells. By using CRISPR/Cas9-mediated gene knockout, we verified that the depletion of endogenous ErbB4 improved the VM formation capability. Although treatment with neuregulin 1 (NRG1), a ligand of ErbB4, induced the phosphorylation of ErbB4 and promoted VM formation in a dose-dependent manner, it did not induce such activities in kinase-dead K751M ErbB4-overexpressing cells. Moreover, we examined the effect of the missense mutation E872K of ErbB4, which has been reported in multiple tumors, on VM formation, and found that the mutation enhanced the basal phosphorylation level and ErbB4-mediated VM formation in the absence of NRG1 stimulation. Whereas NRG1 stimulated VM formation, excessive activation of ErbB4 induced a negative effect. In E872K ErbB4-overexpressing cells, but not in wild-type ErbB4-overexpressing cells, the number of VM tubes was significantly decreased by low-dose treatment with the ErbB inhibitor afatinib. Taken together, our findings demonstrated the significance of ErbB4-mediated VM formation, and suggested the possibility of ErbB4 mutations as effective targets in breast cancer.

  • Methionine aminopeptidase-2 is a pivotal regulator of vasculogenic mimicry

    Shimizu S., Kawahara R., Simizu S.

    Oncology Reports (Oncology Reports)  47 ( 2 )  2022.02

    ISSN  1021335X

    　View Summary

    Vasculogenic mimicry (VM) is the formation of a blood supply system that confers aggressive and metastatic properties to tumors and correlates with a poor prognosis in cancer patients. Thus, the inhibition of VM is considered an effective approach for cancer treatment, although such a mechanism remains poorly described. In the present study, we examined methionine aminopeptidase-2 (MetAP2), a key factor of angiogenesis, and demonstrated that it is pivotal for VM, using pharmacological and genetic approaches. Fumagillin and TNP-470, angiogenesis inhibitors that target MetAP2, significantly suppressed VM in various human cancer cell lines. We established MetAP2-knockout (KO) human fibrosarcoma HT1080 cells using the CRISPR/Cas9 system and found that VM was attenuated in these cells. Furthermore, re-expression of wild-type MetAP2 restored VM in the MetAP2-KO HT1080 cells, but the substitution of D251, a conserved amino acid in MetAP2, failed to rescue the VM. Collectively, our results demonstrate that MetAP2 is critical for VM in human cancer cells and suggest fumagillin and TNP-470 as potent VM-suppressing agents.

  • Gilteritinib overcomes lorlatinib resistance in ALK-rearranged cancer

    Mizuta H., Okada K., Araki M., Adachi J., Takemoto A., Kutkowska J., Maruyama K., Yanagitani N., Oh-hara T., Watanabe K., Tamai K., Friboulet L., Katayama K., Ma B., Sasakura Y., Sagae Y., Kukimoto-Niino M., Shirouzu M., Takagi S., Simizu S., Nishio M., Okuno Y., Fujita N., Katayama R.

    Nature Communications (Nature Communications)  12 ( 1 )  2021.12

    　View Summary

    ALK gene rearrangement was observed in 3%–5% of non-small cell lung cancer patients, and multiple ALK-tyrosine kinase inhibitors (TKIs) have been sequentially used. Multiple ALK-TKI resistance mutations have been identified from the patients, and several compound mutations, such as I1171N + F1174I or I1171N + L1198H are resistant to all the approved ALK-TKIs. In this study, we found that gilteritinib has an inhibitory effect on ALK-TKI–resistant single mutants and I1171N compound mutants in vitro and in vivo. Surprisingly, EML4-ALK I1171N + F1174I compound mutant-expressing tumors were not completely shrunk but regrew within a short period of time after alectinib or lorlatinib treatment. However, the relapsed tumor was markedly shrunk after switching to the gilteritinib in vivo model. In addition, gilteritinib was effective against NTRK-rearranged cancers including entrectinib-resistant NTRK1 G667C-mutant and ROS1 fusion-positive cancer.

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Papers, etc., Registered in KOARA 【 Display / hide 】

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Reviews, Commentaries, etc. 【 Display / hide 】

  • Vasculogenic mimicry: A dynamic event of malignancy

    Simizu S.

    Biochimica et Biophysica Acta - General Subjects (Biochimica et Biophysica Acta - General Subjects)  1866 ( 3 )  2022.03

    ISSN  03044165

  • C-Mannosylation: Previous studies and future research perspectives

    Niwa Y., Simizu S.

    Trends in Glycoscience and Glycotechnology (Trends in Glycoscience and Glycotechnology)  30 ( 177 ) E231 - E238 2018.11

    ISSN  09157352

    　View Summary

    © 2018 FCCA (Forum: Carbohydrates Coming of Age). C-linked glycosylation, one of the protein glycosylations, is a unique type of glycosylation in which an α-mannose is attached to the indole C2 carbon of a tryptophan residue via a C–C linkage and is so named C-mannosylation. C-mannosylation is enzymati-cally catalyzed in the endoplasmic reticulum (ER) lumen, and the N-terminal side Trp residue of the consensus amino acid sequence Trp-Xaa-Xaa-Trp/Cys (Xaa represents any amino acid) is often C-mannosylated. It has been reported that about 30 proteins are C-mannosylated, and the functions of C-mannosylation are becoming clear. In 2013, C. elegans dumpy-19 (dpy-19) was identified as a C-mannosyltransferase, and we revealed that DPY19L3, one of the human homologs of dpy-19, has similar activity in 2016. In this review, we describe previous studies about C-mannosylation, including our results and future research perspectives.

  • C-Mannosylation: Previous studies and future research perspectives

    Niwa Y., Simizu S.

    Trends in Glycoscience and Glycotechnology (Trends in Glycoscience and Glycotechnology)  30 ( 177 )  2018.11

    ISSN  09157352

    　View Summary

    © 2018 FCCA (Forum: Carbohydrates Coming of Age). C-linked glycosylation, one of the protein glycosylations, is a unique type of glycosylation in which an α-mannose is attached to the indole C2 carbon of a tryptophan residue via a C–C linkage and is so named C-mannosylation. C-mannosylation is enzymati-cally catalyzed in the endoplasmic reticulum (ER) lumen, and the N-terminal side Trp residue of the consensus amino acid sequence Trp-Xaa-Xaa-Trp/Cys (Xaa represents any amino acid) is often C-mannosylated. It has been reported that about 30 proteins are C-mannosylated, and the functions of C-mannosylation are becoming clear. In 2013, C. elegans dumpy-19 (dpy-19) was identified as a C-mannosyltransferase, and we revealed that DPY19L3, one of the human homologs of dpy-19, has similar activity in 2016. In this review, we describe previous studies about C-mannosylation, including our results and future research perspectives.

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Presentations 【 Display / hide 】

  • R-spondin1 におけるリン酸化の機能解析

    西谷 拓海, 鈴木 健裕, 丹羽 祐貴, 三浦 一輝, 堂前 直, 清水 史郎

    日本農芸化学会関東支部会2018年度大会 (千葉) , 

    2018.10
    , 

    Poster presentation

  • Vibsanin A誘導体の生物活性評価および標的分子の同定

    三浦 一輝、松木 渉、高尾 賢一、清水 史郎

    日本農芸化学会関東支部会2018年度大会　 (千葉) , 

    2018.10
    , 

    Poster presentation

  • ヒトC型糖転移酵素DPY19L3のプロモーター解析

    吉本 哲、三浦 一輝、清水 史郎

    日本農芸化学会関東支部会2018年度大会　 (千葉) , 

    2018.10
    , 

    Poster presentation

  • トポロジー解析によるDPY19L1のC-mannosyltransferase活性中心の探索

    横山 典弘, 柳原 凌太郎, 三浦 一輝, 丹羽 祐貴, 清水 史郎

    日本農芸化学会関東支部会2018年度大会 (千葉) , 

    2018.10
    , 

    Poster presentation

  • C-mannosylation－基質と酵素の探索

    清水 史郎

    日本農芸化学会中部支部 第183回例会 (名古屋) , 

    2018.09
    , 

    Symposium, workshop panel (nominated)

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Research Projects of Competitive Funds, etc. 【 Display / hide 】

  • Role of C-mannosylation in zebrafish and development of inhibitors for C-mannosylation

    2024.04
    -
    2027.03

    基盤研究(C), Principal investigator

  • 新たなC型糖修飾責任酵素の同定と基質タンパク質の解析

    2018.04
    -
    2021.03

    MEXT,JSPS, Grant-in-Aid for Scientific Research, Grant-in-Aid for Scientific Research (C), Principal investigator

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Awards 【 Display / hide 】

  • 日本がん転移学会　研究奨励賞

    SIMIZU Siro, 2012.07, 日本がん転移学会, ケミカルバイオロジーによる転移関連分子の理解と制御

    Type of Award： Award from Japanese society, conference, symposium, etc.

  • B.B.B.論文賞

    MIYAZAKI Isao, SIMIZU Siro, ICHIMIYA Harumi, KAWATANI Makoto, OSADA Hiroyuki, 2009.03, 日本農芸化学会, Robust and systematic drug screening method using chemical arrays and the protein library: identification of novel inhibitors of carbonic anhydrase II

    Type of Award： Award from Japanese society, conference, symposium, etc.

  • 日本癌学会奨励賞

    SIMIZU Siro, 2004.10, 日本癌学会, 薬剤耐性・転移に関与するがん分子標的の機能解析

    Type of Award： Award from Japanese society, conference, symposium, etc.

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Courses Taught 【 Display / hide 】

  • MICROBIOLOGY

    2024

  • LABORATORIES IN APPLIED CHEMISTRY D

    2024

  • INDEPENDENT STUDY ON FUNDAMENTAL SCIENCE AND TECHNOLOGY

    2024

  • GRADUATE RESEARCH ON FUNDAMENTAL SCIENCE AND TECHNOLOGY 2

    2024

  • GRADUATE RESEARCH ON FUNDAMENTAL SCIENCE AND TECHNOLOGY 1

    2024

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Memberships in Academic Societies 【 Display / hide 】

  • The Japanese Society of Carbohydrate Research, 

    2015
    -
    Present

  • 日本がん分子標的治療学会, 

    2009
    -
    Present

  • 日本ケミカルバイオロジー学会, 

    2008
    -
    Present

  • 日本がん転移学会, 

    2006
    -
    Present

  • 日本癌学会, 

    1992
    -
    Present
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Committee Experiences 【 Display / hide 】

  • 2015
    -
    Present

    Member, 日本がん転移学会

  • 2009
    -
    Present

    Board of Councillors, 日本がん分子標的治療学会

  • 2008
    -
    Present

    Member, 日本ケミカルバイオロジー学会

  • 1992
    -
    Present

    Member, 日本癌学会

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