加藤 優 (カトウ ユウ)

Kato, Yu

写真a

所属(所属キャンパス)

薬学部 薬学科 化学療法学講座 (芝共立)

職名

助教

メールアドレス

メールアドレス

研究室住所

東京都港区芝公園1-5-30

研究室電話番号

03-5400-2669

研究室FAX番号

03-5400-2669

学歴 【 表示 / 非表示

  • 2009年04月
    -
    2015年03月

    慶應義塾, 薬学部

    日本, 大学, 卒業

  • 2015年04月
    -
    2019年03月

    慶應義塾, 薬学部, 薬学研究科

    大学院, 修了, 博士

学位 【 表示 / 非表示

  • 博士(薬学), 慶應義塾, 課程, 2019年03月

免許・資格 【 表示 / 非表示

  • 薬剤師, 2015年05月

 

研究分野 【 表示 / 非表示

  • 医療系薬学

研究キーワード 【 表示 / 非表示

  • がん代謝

  • 上皮間葉転換

  • 分子標的薬

研究テーマ 【 表示 / 非表示

  • EMTにおけるside population細胞の誘導, 

    2019年04月
    -
    継続中

  • がん特異的な代謝ストレス応答に関する研究, 

    2015年04月
    -
    継続中

 

論文 【 表示 / 非表示

  • GZD824 inhibits GCN2 and sensitizes cancer cells to amino acid starvation stress

    Kato Y., Kunimasa K., Takahashi M., Harada A., Nagasawa I., Osawa M., Sugimoto Y., Tomida A.

    Molecular Pharmacology (Molecular Pharmacology)  98 ( 6 ) 669 - 676 2020年12月

    ISSN  0026895X

     概要を見る

    © 2020 by The American Society for Pharmacology and Experimental Therapeutics. Eukaryotic initiation factor 2a (eIF2a) kinase general control nonderepressible 2 (GCN2) drives cellular adaptation to amino acid limitation by activating the integrated stress response that induces activating transcription factor 4 (ATF4). Here, we found that a multikinase inhibitor, GZD824, which we identified using a cell-based assay with ATF4 immunostaining, inhibited the GCN2 pathway in cancer cells. Indeed, GZD824 suppressed GCN2 activation, eIF2a phosphorylation, and ATF4 induction during amino acid starvation stress. However, at lower nonsuppressive concentrations, GZD824 paradoxically stimulated eIF2a phosphorylation and ATF4 expression in a GCN2-dependent manner under unstressed conditions. Such dual properties conceivably arose from a direct effect on GCN2, as also observed in a cell-free GCN2 kinase assay and shared by a selective GCN2 inhibitor. Consistent with the GCN2 pathway inhibition, GZD824 sensitized certain cancer cells to amino acid starvation stress similarly to ATF4 knockdown. These results establish GZD824 as a multikinase GCN2 inhibitor and may enhance its utility as a drug under development.

  • Effect of TNIK upregulation on JQ1-resistant human colorectal cancer HCT116 cells

    Takahashi C., Kondo S., Sadaoka K., Ishizuka S., Noguchi K., Kato Y., Sugimoto Y.

    Biochemical and Biophysical Research Communications (Biochemical and Biophysical Research Communications)  530 ( 1 ) 230 - 234 2020年09月

    ISSN  0006291X

     概要を見る

    © 2020 Elsevier Inc. JQ1 disrupts the binding of bromodomain and extra-terminal (BET) family of proteins to acetylated histones, modulates the expression of various genes, and inhibits the proliferation of cancer cells. We established two JQ1-resistant sublines from human colorectal cancer HCT116 cells. These resistant cells showed an 8- to 9-fold higher resistance to JQ1, and a 2- to 4-fold higher resistance to various anti-cancer agents, such as doxorubicin, etoposide, mitoxantrone, SN-38, cisplatin, and methotrexate than the parental HCT116 cells. The JQ1-resistant cells expressed higher levels of TRAF2 and NCK-interacting protein kinase (TNIK), cyclin D1 (CCND1), cyclin E1 (CCNE1), and their corresponding mRNAs than the parental cells. TNIK is a regulator of Wnt/β-catenin signaling and is known to transactivate CCND1. Transient transfection of HCT116 cells with a TNIK expression plasmid resulted in the upregulation of cyclin D1, cyclin E1, and their corresponding mRNAs, as well as an increase in CCNE1 promoter activity. Furthermore, luciferase assay revealed that the JQ1-resistant cells showed high CCNE1 promoter activity. These results suggest that TNIK also transactivates CCNE1. Three stable TNIK transfectant clones of HEK293 cells expressed 1.5- to 2-fold higher levels of TNIK, cyclin D1, and cyclin E1 than the parental cells. The 293/TNIK-6 cells, which expressed the highest level of TNIK among the transfectants, showed a 2.3-fold higher resistance to JQ1 than the parental cells. These results suggest the possible involvement of TNIK in cellular resistance to JQ1.

  • STAT1 upregulates glutaminase and modulates amino acids and glutathione metabolism

    Shingo Kondo, Yu Kato, Satoshi Minagawa, Yoshikazu Sugimoto

    Biochemical and Biophysical Research Communications (Biochemical and Biophysical Research Communications)  523 ( 3 ) 672 - 677 2020年01月

    研究論文(学術雑誌), 共著, 査読有り,  ISSN  0006291X

     概要を見る

    © 2020 Elsevier Inc. We previously reported the upregulation of cellular Glu and glutathione levels in human ABCB5- and murine Abcb5-transfected cells. Here, we demonstrate the upregulation of STAT1 and glutaminase (GLS) in ABCB5/Abcb5-transfected cells. Among a total of four ABCB5/Abcb5 high-expressing clones with docetaxel resistance, three of the clones expressed STAT1 and GLS highly and showed resistance to docetaxel and buthionine sulfoximine (BSO), an inhibitor of glutathione synthesis. Neither STAT1 nor GLS upregulation was observed in the remaining ABCB5 high-expressing clone, as well as in another two ABCB5 low-expressing clones; these three clones did not show BSO resistance. The ABCB5/STAT1 high-expressing clones showed higher cellular levels of Ala, Glu, and Asp and lower cellular levels of Phe, Trp, Leu, Ile, Gly, Met, Tyr, Val, and His compared to the ABCB5/STAT1 low-expressing clones. The former clones also showed a higher resistance to Glu. The STAT1-transfected clones expressed high levels of GLS and the corresponding mRNA, suggesting the transactivation of GLS by STAT1. These clones showed resistance to Glu and BSO, similar to the ABCB5/STAT1 high-expressing clones. The cellular glutathione levels of the STAT1-transfected clones were significantly higher than that of the control. The STAT1-transfected clones also showed greater resistance to the effect of BSO on the cellular glutathione depletion compared to the control. These results demonstrate that STAT1 upregulates GLS and modulates amino acids and glutathione metabolism. Although we were unable to directly prove STAT1 upregulation by ABCB5, our results suggest that ABCB5 expression, directly or indirectly, leads to the overexpression of STAT1.

  • SNAIL- and SLUG-induced side population phenotype of HCT116 human colorectal cancer cells and its regulation by BET inhibitors

    Kato Y., Kondo S., Itakura T., Tokunaga M., Hatayama S., Katayama K., Sugimoto Y.

    Biochemical and Biophysical Research Communications (Biochemical and Biophysical Research Communications)  521 ( 1 ) 152 - 157 2019年

    研究論文(学術雑誌), 単著, 査読有り,  ISSN  0006291X

     概要を見る

    © 2019 Elsevier Inc. Epithelial-mesenchymal transition (EMT) is associated with cancer malignancies such as invasion, metastasis, and drug resistance. In this study, HCT116 human colorectal cancer cells were transduced with SLUG or SNAIL retroviruses, and EMT cells with mesenchymal morphology were established. The EMT cells showed a high invasive activity and resistance to several anticancer agents such as methotrexate, SN-38, and cisplatin. Furthermore, they contained about 1–10% side population (SP) cells that were not stained by Hoechst 33342. This SP phenotype was not stable; the isolated SP cells generated both SP and non-SP cells, suggesting a potential for differentiation. Gene expression analysis of SP cells suggested the alteration of genes that are involved in epigenetic changes. Therefore, we examined the effect of 74 epigenetic inhibitors, and found that two inhibitors, namely I-BET151 and bromosporine, targeting the bromodomain and extra-terminal motif (BET) proteins, decreased the ratio of SP cells to <50% compared with the control, without affecting the immediate efflux of Hoechst 33342 by transporters. In addition, compared with the parental cells, the EMT cells showed a higher sensitivity to I-BET151 and bromosporine. This study suggests that EMT development and SP phenotype can be independent events but both are regulated by BET inhibitors in SLUG- or SNAIL-transducted HCT116 cells.

  • BCR-ABL tyrosine kinase inhibition induces metabolic vulnerability by preventing the integrated stress response in K562 cells

    Kato Y., Kunimasa K., Sugimoto Y., Tomida A.

    Biochemical and Biophysical Research Communications (Biochemical and Biophysical Research Communications)  504 ( 4 ) 721 - 726 2018年10月

    ISSN  0006291X

     概要を見る

    © 2018 Elsevier Inc. The integrated stress response (ISR) is a cellular process that is characterized by activation of eukaryotic initiation factor (eIF)2α kinases and subsequent induction of activating transcription factor (ATF)4. The ISR plays an important role in protecting cells from tumor-related metabolic stresses, such as nutrient deprivation and perturbed proteostasis. Here, we showed that disruption of the ISR, together with increased cellular stress vulnerability, was produced by pharmacological inhibition of BCR-ABL, the oncogenic driver in chronic myeloid leukemia (CML). Treatment of CML-derived K562 cells with BCR-ABL tyrosine kinase inhibitors, including imatinib, dasatinib, nilotinib and ponatinib, prevented activation of eIF2α kinases, protein kinase-like endoplasmic reticulum kinase (PERK) and general control nonderepressible 2, and downstream ATF4 induction during metabolic stress. Prevention of ATF4 induction likely occurred as a result of the combinatorial suppression of the eIF2α kinase and phosphoinositide 3-kinase/mammalian target of rapamycin signaling pathways. In addition, we found that pharmacological inhibition of PERK mimicked BCR-ABL inhibition to enhance apoptosis induction under stress conditions. These findings indicate that the ISR is under the control of BCR-ABL and may foster adaptation to tumorigenic stresses in CML cells.

研究発表 【 表示 / 非表示

  • ABCB5発現細胞におけるGLS発現の増大

    第78回 日本癌学会学術集会, 2019年09月, ポスター(一般)

  • 上皮間葉転換に伴って誘導されるside population細胞の制御

    第78回 日本癌学会学術集会, 2019年09月, ポスター(一般)

  • FLT3-ITDによるIntegrated Stress Responseの制御

    第63回 日本薬学会 関東支部大会, 2019年09月, ポスター(一般)

  • P-glycoproteinの発現を制御するタンパク質の探索

    第63回 日本薬学会 関東支部大会, 2019年09月, ポスター(一般)

  • JQ1耐性細胞の解析

    第63回 日本薬学会関東支部大会, 2019年09月, ポスター(一般)

全件表示 >>

競争的資金等の研究課題 【 表示 / 非表示

  • 細胞転換によるがん細胞の薬剤感受性化メカニズムの解析

    2020年04月
    -
    2023年03月

    文部科学省・日本学術振興会, 科学研究費助成事業, 加藤 優, 若手研究, 補助金,  代表

 

担当授業科目 【 表示 / 非表示

  • 課題研究(化学療法学)

    2020年度

  • 演習(化学療法学)

    2020年度

  • 卒業研究1(薬学科)

    2020年度

  • 英語演習(薬学科)

    2020年度

  • 微生物学実習

    2020年度

全件表示 >>