Kato, Yu



Faculty of Pharmacy, Department of Pharmacy Division of Molcular Oncological Pharmacy (Shiba-Kyoritsu)


Research Associate/Assistant Professor/Instructor

Contact Address

1-5-30 Shibakoen, Minato-ku, Tokyo

Telephone No.


Fax No.


Academic Background 【 Display / hide

  • 2009.04

    Keio University, faculty of pharmacy

    University, Graduated

  • 2015.04

    Keio University, 薬学部, 薬学研究科

    Graduate School, Completed, Doctoral course

Academic Degrees 【 Display / hide

  • Doctor of Pharmaceutical Sciences, Keio University, Coursework, 2019.03

Licenses and Qualifications 【 Display / hide

  • pharmacist, 2015.05


Research Areas 【 Display / hide

  • Life Science / Clinical pharmacy

Research Keywords 【 Display / hide

  • がん代謝

  • Epithelial mesenchymal transition

  • 分子標的薬

Research Themes 【 Display / hide

  • Elucidation of the mechanism of drug sensitivity fluctuation in cell transition, 


  • EMTにおけるside population細胞の誘導, 


  • がん特異的な代謝ストレス応答に関する研究, 



Papers 【 Display / hide

  • Activating mutations in EGFR and PI3K promote ATF4 induction for NSCLC cell survival during amino acid deprivation

    Takahashi M., Okamoto Y., Kato Y., Shirahama H., Tsukahara S., Sugimoto Y., Tomida A.

    Heliyon (Heliyon)  9 ( 4 )  2023.04

    Research paper (scientific journal), Accepted,  ISSN  24058440

     View Summary

    Some oncoproteins along with stress kinase general control non-derepressible 2 (GCN2) can ensure the induction of activating transcription factor 4 (ATF4) to counteract amino acid deprivation; however, little is known regarding the role of the oncogenic EGFR-PI3K pathway. In this study, we demonstrate that both mutated EGFR and PIK3CA contribute to ATF4 induction following GCN2 activation in NSCLC cells. The inhibition of EGFR or PI3K mutant proteins, pharmacologically or through genetic knockdown, inhibited ATF4 induction without affecting GCN2 activation. A downstream analysis revealed that the oncogenic EGFR-PI3K pathway may utilize mTOR-mediated translation control mechanisms for ATF4 induction. Furthermore, in NSCLC cells harboring co-mutations in EGFR and PIK3CA, the combined inhibition of these oncoproteins markedly suppressed ATF4 induction and the subsequent gene expression program as well as cell viability during amino acid deprivation. Our findings establish a role for the oncogenic EGFR-PI3K pathway in the adaptive stress response and provide a strategy to improve EGFR-targeted NSCLC therapy.

  • 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 2020.10

    Research paper (scientific journal), Accepted,  ISSN  0026895X

     View Summary

    © 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 2020.09

    Research paper (scientific journal), Accepted,  ISSN  0006291X

     View Summary

    © 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 (Elsevier)  523 ( 3 ) 672 - 677 2020.01

    Research paper (scientific journal), Joint Work, Accepted,  ISSN  0006291X

     View Summary

    © 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.

    Yu Kato, Shingo Kondo, Taira Itakura, Miku Tokunaga, Shiori Hatayama, Kazuhiro Katayama, Yoshikazu Sugimoto

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

    Research paper (scientific journal), Lead author, Corresponding author, Accepted,  ISSN  0006291X

     View Summary

    © 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.

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

Presentations 【 Display / hide

  • Bioinfomatics-based identification for factors regulating anti-tumor immunity




    Oral presentation (general)

  • ヒト結腸がん細胞株の上皮間様転換に伴うグルタミナーゼ阻害剤高感受性と ATF4 の発現低下


    第27回日本がん分子標的治療学会学術集会 (佐賀) , 


    Oral presentation (general)

  • 上皮間様転換に伴うglutathione peroxidase 4阻害剤感受性の変動




    Poster presentation

  • SYDE1はSW620細胞のP-gpの発現を上昇させる


    第81回 日本癌学会学術総会, 


    Poster presentation

  • FLT3-ITDによるGCN2経路を介したATF4の発現誘導




    Oral presentation (general)

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

  • 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


    MEXT,JSPS, Grant-in-Aid for Scientific Research, Grant-in-Aid for Early-Career Scientists , Principal investigator


Courses Taught 【 Display / hide











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