Nagano, Osamu

写真a

Affiliation

School of Medicine, Institute for Advanced Medical Research (Division of Gene Regulation) (Shinanomachi)

Position

Associate Professor

External Links

Career 【 Display / hide

  • 1999.06
    -
    2001.03

    Kyushu University Faculty of Dental Science, resident

  • 2007.04
    -
    2012.03

    Keio University School of Medicine, assistant professor

  • 2012.04
    -
    2018.04

    Keio University School of Medicine, assistant professor

  • 2018.05
    -
    Present

    Keio University School of Medicine, associate professor

Academic Background 【 Display / hide

  • 1993.04
    -
    1999.03

    Hiroshima University, Faculty of dentistry

    University, Graduated

  • 2001.04
    -
    2005.03

    Kumamoto University, School of medicine

    Graduate School, Completed, Doctoral course

Academic Degrees 【 Display / hide

  • 医学博士, Kumamoto University, Coursework, 2005.03

    接着分子CD44を介した細胞とマトリックスの相互作用は細胞外カルシウムの流入とPKC活性化によって互いに異なるメタロプロテアーゼを介して制御される

 

Research Areas 【 Display / hide

  • Pathological medical chemistry

Research Keywords 【 Display / hide

  • Tumor biology

 

Papers 【 Display / hide

  • The vasodilator oxyfedrine inhibits aldehyde metabolism and thereby sensitizes cancer cells to xCT-targeted therapy.

    Otsuki Y, Yamasaki J, Suina K, Okazaki S, Koike N, Saya H, Nagano O

    Cancer science (Cancer Science)  111 ( 1 ) 127 - 136 2019.11

    Accepted,  ISSN  1347-9032

     View Summary

    © 2019 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association. The major cellular antioxidant glutathione (GSH) protects cancer cells from oxidative damage that can lead to the induction of ferroptosis, an iron-dependent form of cell death triggered by the aberrant accumulation of lipid peroxides. Inhibitors of the cystine-glutamate antiporter subunit xCT, which mediates the uptake of extracellular cystine and thereby promotes GSH synthesis, are thus potential anticancer agents. However, the efficacy of xCT-targeted therapy has been found to be diminished by metabolic reprogramming that affects redox status in cancer cells. Identification of drugs for combination with xCT inhibitors that are able to overcome resistance to xCT-targeted therapy might thus provide the basis for effective cancer treatment. We have now identified the vasodilator oxyfedrine (OXY) as a sensitizer of cancer cells to GSH-depleting agents including the xCT inhibitor sulfasalazine (SSZ). Oxyfedrine contains a structural motif required for covalent inhibition of aldehyde dehydrogenase (ALDH) enzymes, and combined treatment with OXY and SSZ was found to induce accumulation of the cytotoxic aldehyde 4-hydroxynonenal and cell death in SSZ-resistant cancer cells both in vitro and in vivo. Microarray analysis of tumor xenograft tissue showed cyclooxygenase-2 expression as a potential biomarker for the efficacy of such combination therapy. Furthermore, OXY-mediated ALDH inhibition was found to sensitize cancer cells to GSH depletion induced by radiation therapy in vitro. Our findings thus establish a rationale for repurposing of OXY as a sensitizing drug for cancer treatment with agents that induce GSH depletion.

  • Epigenomic profiling discovers trans-lineage SOX2 partnerships driving tumor heterogeneity in lung squamous cell carcinoma.

    Sato T, Yoo S, Kong R, Sinha A, Chandramani-Shivalingappa P, Patel A, Fridrikh M, Nagano O, Masuko T, Beasley MB, Powell CA, Zhu J, Watanabe H

    Cancer research (Cancer Research)  79 ( 24 ) 6084 - 6100 2019.09

    Accepted,  ISSN  0008-5472

     View Summary

    © 2019 American Association for Cancer Research. Molecular characterization of lung squamous cell carcinoma (LUSC), one of the major subtypes of lung cancer, has not sufficiently improved its nonstratified treatment strategies over decades. Accumulating evidence suggests that lineage-specific transcriptional regulators control differentiation states during cancer evolution and underlie their distinct biological behaviors. In this study, by investigating the super-enhancer landscape of LUSC, we identified a previously undescribed "neural" subtype defined by Sox2 and a neural lineage factor Brn2, as well as the classical LUSC subtype defined by Sox2 and its classical squamous partner p63. Robust protein–protein interaction and genomic cooccupancy of Sox2 and Brn2, in place for p63 in the classical LUSC, indicated their transcriptional cooperation imparting this unique lineage state in the "neural" LUSC. Forced expression of p63 downregulated Brn2 in the "neural" LUSC cells and invoked the classical LUSC lineage with more squamous/ epithelial features, which were accompanied by increased activities of ErbB/Akt and MAPK–ERK pathways, suggesting differential dependency. Collectively, our data demonstrate heterogeneous cell lineage states of LUSC featured by Sox2 cooperation with Brn2 or p63, for which distinct therapeutic approaches may be warranted. Significance: Epigenomic profiling reveals a novel subtype of lung squamous cell carcinoma with neural differentiation.

  • Glutaminolysis-related genes determine sensitivity to xCT-targeted therapy in head and neck squamous cell carcinoma.

    Okazaki S, Umene K, Yamasaki J, Suina K, Otsuki Y, Yoshikawa M, Minami Y, Masuko T, Kawaguchi S, Nakayama H, Banno K, Aoki D, Saya H, Nagano O

    Cancer science (Cancer Science)  110 ( 11 ) 3453 - 3463 2019.08

    Accepted,  ISSN  1347-9032

     View Summary

    © 2019 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association. Targeting the function of membrane transporters in cancer stemlike cells is a potential new therapeutic approach. Cystine-glutamate antiporter xCT expressed in CD44 variant (CD44v)-expressing cancer cells contributes to the resistance to oxidative stress as well as cancer therapy through promoting glutathione (GSH)-mediated antioxidant defense. Amino acid transport by xCT might, thus, be a promising target for cancer treatment, whereas the determination factors for cancer cell sensitivity to xCT-targeted therapy remain unclear. Here, we demonstrate that high expression of xCT and glutamine transporter ASCT2 is correlated with undifferentiated status and diminished along with cell differentiation in head and neck squamous cell carcinoma (HNSCC). The cytotoxicity of the xCT inhibitor sulfasalazine relies on ASCT2-dependent glutamine uptake and glutamate dehydrogenase (GLUD)-mediated α-ketoglutarate (α-KG) production. Metabolome analysis revealed that sulfasalazine treatment triggers the increase of glutamate-derived tricarboxylic acid cycle intermediate α-KG, in addition to the decrease of cysteine and GSH content. Furthermore, ablation of GLUD markedly reduced the sulfasalazine cytotoxicity in CD44v-expressing stemlike HNSCC cells. Thus, xCT inhibition by sulfasalazine leads to the impairment of GSH synthesis and enhancement of mitochondrial metabolism, leading to reactive oxygen species (ROS) generation and, thereby, triggers oxidative damage. Our findings establish a rationale for the use of glutamine metabolism (glutaminolysis)-related genes, including ASCT2 and GLUD, as biomarkers to predict the efficacy of xCT-targeted therapy for heterogeneous HNSCC tumors.

  • Glucose transporter 1-mediated vascular translocation of nanomedicines enhances accumulation and efficacy in solid tumors

    Suzuki K., Miura Y., Mochida Y., Miyazaki T., Toh K., Anraku Y., Melo V., Liu X., Ishii T., Nagano O., Saya H., Cabral H., Kataoka K.

    Journal of Controlled Release (Journal of Controlled Release)  301   28 - 41 2019.05

    Accepted,  ISSN  01683659

     View Summary

    © 2019 Elsevier B.V. Nanomedicine modification with ligands directed to receptors on tumor blood vessels has the potential for selectively enhancing nanomedicine accumulation in malignant tissues by overcoming the vascular barrier of tumors. Nevertheless, the development of broadly applicable ligand approaches capable of promoting the transvascular transport of nanomedicines in a wide spectrum of tumors has been elusive so far. By considering the indispensable and persistent glycolytic fueling of tumors, we developed glucose-installed polymeric micelles loading cisplatin (Gluc-CDDP/m) targeting the glucose transporter 1 (GLUT1), which is overexpressed in most tumors and present on vascular endothelial cells, toward improving the delivery efficiency and therapeutic efficacy. The design of the glucose ligands on Gluc-CDDP/m was engineered to control the conjugation via the carbon 6 of the glucose moieties, as well as the ligand density on the poly (ethylene glycol) (PEG) shell of the micelles. The series of micelles was then studied in vitro and in vivo against GLUT1-high human squamous cell carcinoma of the head and neck OSC-19 cells and GLUT1-low human glioblastoma-astrocytoma U87MG cells. Our results showed that precisely tuning the micelles to have glucose ligands on 25% of their PEG chains increased the efficacy against the tumors by significantly enhancing the tumor accumulation, even in GLUT1-low U87MG tumors. The enhancement of the intratumoral levels of these micelles was hindered by concomitant administration of glucose, or the GLUT1 inhibitor STF-31, confirming a GLUT1/glucose-mediated increment of the accumulation. Intravital confocal laser scanning microscopy imaging of tumor tissues further demonstrated the rapid extravasation and penetration of Gluc-CDDP/m in OSC-19 tumors compared to non-targeted CDDP/m. These findings indicate GLUT1-targeting as a promising approach for overcoming the vascular barrier and boosting the delivery of nanomedicine in tumors.

  • Gold-nanofève surface-enhanced Raman spectroscopy visualizes hypotaurine as a robust anti-oxidant consumed in cancer survival

    Shiota Megumi, Naya Masayuki, Yamamoto Takehiro, Hishiki Takako, Tani Takeharu, Takahashi Hiroyuki, Kubo Akiko, Koike Daisuke, Itoh Mai, Ohmura Mitsuyo, Kabe Yasuaki, Sugiura Yuki, Hiraoka Nobuyoshi, Morikawa Takayuki, Takubo Keiyo, Suina Kentaro, Nagashima Hideaki, Sampetrean Oltea, Nagano Osamu, Saya Hideyuki, Yamazoe Shogo, Watanabe Hiroyuki, Suematsu Makoto

    Nature Communications (Nature Communications)  9 ( 1 ) 1561 2018.12

    Accepted,  ISSN  2041-1723

     View Summary

    <p>Gold deposition with diagonal angle towards boehmite-based nanostructure creates random arrays of horse-bean-shaped nanostructures named gold-nanofève (GNF). GNF generates many electromagnetic hotspots as surface-enhanced Raman spectroscopy (SERS) excitation sources, and enables large-area visualization of molecular vibration fingerprints of metabolites in human cancer xenografts in livers of immunodeficient mice with sufficient sensitivity and uniformity. Differential screening of GNF-SERS signals in tumours and those in parenchyma demarcated tumour boundaries in liver tissues. Furthermore, GNF-SERS combined with quantum chemical calculation identified cysteine-derived glutathione and hypotaurine (HT) as tumour-dominant and parenchyma-dominant metabolites, respectively. CD44 knockdown in cancer diminished glutathione, but not HT in tumours. Mechanisms whereby tumours sustained HT under CD44-knockdown conditions include upregulation of PHGDH, PSAT1 and PSPH that drove glycolysis-dependent activation of serine/glycine-cleavage systems to provide one-methyl group for HT synthesis. HT was rapidly converted into taurine in cancer cells, suggesting that HT is a robust anti-oxidant for their survival under glutathione-suppressed conditions.</p>

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

Presentations 【 Display / hide

  • Cancer treatment strategy targeting antioxidant system potentiated by CD44v-xCT in stem-like cancer cells.

    Nagano Osamu

    BioMedical Transporters 2017, 2017.08, Symposium, Workshop, Panelist (nomination)

  • Cancer treatment strategy targeting antioxidant system potentiated by CD44v-xCT in stem-like cancer cells.

    Nagano Osamu

    ALBERTA-JAPAN AGENCY FOR MEDICAL RESEARCH AND DEVELOPMENT (AMED) WORKSHOP FOR MEDICAL INNOVATION, 2017.02, Symposium, Workshop, Panelist (public offering), Alberta, Canada

  • CD44v-xCTを介した抗酸化システムを標的とする癌治療法

    Nagano Osamu

    第14回日本臨床腫瘍学会学術集会 (神戸国際会議場) , 2016.07, Symposium, Workshop, Panelist (public offering)

  • 癌幹細胞において活性化されるCD44v-xCTを介した抗酸化システムを標的とする癌治療戦略

    Nagano Osamu

    第11回日本がん分子標的学会トランスレーショナルリサーチワークショップ, 2016.01, Symposium, Workshop, Panelist (public offering)

  • Cancer treatment strategy targeting antioxidant system potentiated by CD44v-xCT in stem-like cancer cells

    Nagano Osamu

    第74回日本癌学会学術総会, 2015.10, Symposium, Workshop, Panelist (public offering)

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

  • Elucidation of the mechanism of the induction of ferroptosis by xCT inhibitor and its antitumor effect in small cell lung cancer

    2017.04
    -
    2020.03

    MEXT,JSPS, Grant-in-Aid for Scientific Research, 永野 修, Grant-in-Aid for Scientific Research (B), Principal Investigator

Intellectual Property Rights, etc. 【 Display / hide

  • 抗腫瘍剤及び配合剤

    Application No.: 特願2017-220231  2017.11 

    Patent, Joint, National application

  • がん幹細胞の増殖抑制剤および細胞内活性酸素蓄積誘導剤

    Application No.: PCT/JP2015/051761  2015.01 

    Announcement No.: WO2015/115310  2015.08 

    Patent, Joint, PCT international application

  • ダイヤモンドマイクロ電極を用いた生体内pH測定装置及び方法

    Application No.: 2013-172401  2013.08 

    Announcement No.: 2015-039544  2015.03 

    Patent, Joint, National application

  • ダイヤモンド微小電極を用いた還元型グルタチオンの測定装置

    Application No.: 2012-080323  2012.03 

    Announcement No.: 2013-208259  2013.10 

    Patent, Joint, National application

Awards 【 Display / hide

  • Incitement Award of the Japanese Cancer Association

    2011.10, Japanese cancer association, 癌幹細胞マーカーCD44の機能解析

 

Memberships in Academic Societies 【 Display / hide

  • Japanese Cancer Association, 

    2003.09
    -
    Present