Role of cystine/glutamate transporter in cancer metastasis.

• Project/Area Number: 17K07158
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Tumor biology
• Research Institution: Niigata University
• Principal Investigator: Sato Hideyo 新潟大学, 医歯学系, 教授 (60235380)
• Co-Investigator(Kenkyū-buntansha): 岡田 太 鳥取大学, 医学部, 教授 (00250423)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2019: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2017: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: シスチン・グルタミン酸トランスポーター / グルタチオン / シスチン / メラノーマ / 転移 / グルタミン酸 / xCT / 転移能 / 遊走能 / 肉腫 / ヒト肉芽腫 / ｘCT / 浸潤 / アミノ酸トランスポーター / がん / 浸潤・転移

Outline of Final Research Achievements

In order to clarify the function of cystine/glutamate transporter (xCT) in cancer cell invasion and metastasis, xCT of mouse melanoma with high metastatic potential was knocked out using CRISPR/Cas9 system. The effect of xCT deficiency on the metastasis was investigated using several metastasis models. As a result, xCT knockout cells were shown to have a significantly reduced metastatic potential as compared to wild type cells. Accordingly, it was shown that the survival rate of the mice transplanted with xCT knockout cells was significantly higher than that of the mice transplanted with wild-type cells. These findings indicate that xCT has an important role in cancer metastasis.

Academic Significance and Societal Importance of the Research Achievements

本研究により、シスチン・グルタミン酸トランスポーターは、がん細胞の浸潤や転移に重要な役割を担うことが示された。このことは、シスチン・グルタミン酸トランスポーターが、がんの治療において、新しいターゲット分子なることを示している。このトランスポーターの阻害剤の開発が進めば、がんの転移を抑制する新規のがん治療法となることが期待できる。

Research Products

• [Int'l Joint Research] Helmholtz Institute(ドイツ)
• [Int'l Joint Research] ヘルムホルツ研究所(ドイツ)
• [Int'l Joint Research] Brije大学(ベルギー)
• [Journal Article] Genetic and pharmacological manipulation of glial glutamate transporters does not alter infection-induced seizure activity (2019)
  • Author(s): Loewen Jaycie L.、Albertini Giulia、Dahle E. Jill、Sato Hideyo、Smolders Ilse J.、Massie Ann、Wilcox Karen S.
  • Journal Title: Experimental Neurology Volume: 318 Pages: 50-60
  • DOI: 10.1016/j.expneurol.2019.04.010
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] System xc? in microglia is a novel therapeutic target for post-septic neurological and psychiatric illness (2019)
  • Author(s): Kitagawa Yoshinori、Nakaso Kazuhiro、Horikoshi Yosuke、Morimoto Masaki、Omotani Takuma、Otsuki Akihiro、Inagaki Yoshimi、Sato Hideyo、Matsura Tatsuya
  • Journal Title: Scientific Reports Volume: 9 Issue: 1 Pages: 1-13
  • DOI: 10.1038/s41598-019-44006-8
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Anticonvulsant and antiepileptogenic effects of system xc? inactivation in chronic epilepsy models (2019)
  • Author(s): Leclercq Karine、Liefferinge Joeri Van、Albertini Giulia、Neveux Michel、Dardenne Sylvia、Mairet‐Coello Georges、Vandenplas Catherine、Deprez Tania、Chong Seon‐Ah、Foerch Patrik、Bentea Eduard、Sato Hideyo、Maher Pamela、Massie Ann、Smolders Ilse、Kaminski Rafal M.
  • Journal Title: Epilepsia Volume: 60 Issue: 7 Pages: 1412-1423
  • DOI: 10.1111/epi.16055
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] The ferroptosis inducer erastin irreversibly inhibits system xc- and synergizes with cisplatin to increase cisplatin’s cytotoxicity in cancer cells. (2018)
  • Author(s): Sato, M., Kusumi, R., Hamashima, S., Kobayashi, S., Sasaki, S., Komiyama, Y., Izumikawa, T., Conrad, M., Bannai, S., and Sato. H.
  • Journal Title: Sci. Rep. Volume: 8 Issue: 1 Pages: 968-968
  • DOI: 10.1038/s41598-018-19213-4
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] The cystine-glutamate exchanger (xCT, Slc7a11) is expressed in significant concentrations in a subpopulation of astrocytes in the mouse brain (2018)
  • Author(s): Ottestad-Hansen Sigrid、Hu Qiu Xiang、Follin-Arbelet Virgine Veronique、Bentea Eduard、Sato Hideyo、Massie Ann、Zhou Yun、Danbolt Niels Christian
  • Journal Title: Glia Volume: 66 Issue: 5 Pages: 951-970
  • DOI: 10.1002/glia.23294
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Cystine/glutamate transporter, system x c- , is involved in nitric oxide production in mouse peritoneal macrophages (2018)
  • Author(s): Kobayashi S、Hamashima S、Homma T、Sato M、Kusumi R、Bannai S、Fujii J、Sato H
  • Journal Title: Nitric Oxide Volume: 78 Pages: 32-40
  • DOI: 10.1016/j.niox.2018.05.005
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Macrophages Switch Their Phenotype by Regulating Maf Expression during Different Phases of Inflammation (2018)
  • Author(s): Kikuchi Kenta、Iida Mayumi、Ikeda Naoki、Moriyama Shigetaka、Hamada Michito、Takahashi Satoru、Kitamura Hiroshi、Watanabe Takashi、Hasegawa Yoshinori、Hase Koji、Fukuhara Takeshi、Sato Hideyo、Kobayashi Eri H.、Suzuki Takafumi、Yamamoto Masayuki、Tanaka Masato、Asano Kenichi
  • Journal Title: The Journal of Immunology Volume: 201 Issue: 2 Pages: 635-651
  • DOI: 10.4049/jimmunol.1800040
  • Peer Reviewed / Open Access
• [Journal Article] Genetic deletion of xCT attenuates peripheral and central inflammation and mitigates LPS-induced sickness and depressive-like behavior in mice (2018)
  • Author(s): Albertini Giulia、Deneyer Lauren、Ottestad-Hansen Sigrid、Zhou Yun、Ates Gamze、Walrave Laura、Demuyser Thomas、Bentea Eduard、Sato Hideyo、De Bundel Dimitri、Danbolt Niels C.、Massie Ann、Smolders Ilse
  • Journal Title: Glia Volume: 66 Issue: 9 Pages: 1845-1861
  • DOI: 10.1002/glia.23343
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] The viability of primary hepatocytes in maintained under a low cysteine-glutathione redox state with a marked elevation in ophthalmic acid production. (2017)
  • Author(s): Lee, J., Kang, E. S., Kobayashi, S., Homma, T., Sato, H., Seo, H. G., and Fujii, J.
  • Journal Title: Exp. Cell Res. Volume: 361 Issue: 1 Pages: 178-191
  • DOI: 10.1016/j.yexcr.2017.10.017
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Decreased reproductive performance in xCT-knockout male mice. (2017)
  • Author(s): Hamashima, S., Homma, T., Kobayashi, S., Ishii, N., Kurahashi, T., Watanabe, R., Kimura, N., Sato, H., and Fujii, J.
  • Journal Title: Free Radic. Res. Volume: 51 Issue: 9-10 Pages: 851-860
  • DOI: 10.1080/10715762.2017.1388504
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] The role of system xc- in methamphetamine-induced dopaminergic neurotoxicity in mice. (2017)
  • Author(s): Dang, D. K., Shin, E. J., Tran, H. Q., Kim, D. J., Jeong, J. H., Jang, C. G., Nah, S. Y., Sato, H., Nabeshima, T., Yoneda, Y., and Kim, H. C.
  • Journal Title: Neurochem. Int. Volume: 108 Pages: 254-265
  • DOI: 10.1016/j.neuint.2017.04.013
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Zonisamide attenuates lactacystin-induced parkinsonism in mice without affecting system xc-. (2017)
  • Author(s): Bentea, E., Liefferinge, J. V., Verbruggen, L., Martens, K., Kobayashi, S., Deneyer, L., Demuyser, T., Albertini, G., Maes, K., Sato, H., Smolders, I., Lewerenz, J., and Massie, A.
  • Journal Title: Exp. Neurol. Volume: 290 Pages: 15-28
  • DOI: 10.1016/j.expneurol.2016.12.009
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] xCT deficiency aggravates acetaminophen-induced hepatotoxicity under inhibition of the transsulfuration pathway (2017)
  • Author(s): Eun Sil Kang, Jaeyong Lee, Takujiro Homma, Toshihiro Kurahashi, Sho Kobayashi, Atsunori Nabeshima, Sohsuke Yamada, Han GeuK Seo, Satoshi Miyata, Hideyo Sato, Junichi Fujii
  • Journal Title: Free Radic Res Volume: 51 Issue: 1 Pages: 80-90
  • DOI: 10.1080/10715762.2017.1282157
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Absence of system xc- on immune cells invading the central nervous system alleviates experimental autoimmune encephalitis. (2017)
  • Author(s): Merckx, E., Albertini, G., Paterka, M., Jensen, C., Albrecht, P., Dietrich, M., Liefferinge, J. V., Bentea, E., Verbruggen, L., Demuyser, T., Deneyer, L, Lewerenz, J., Loo, G. V., Keyser, J. D., Sato, H., Maher, P., Methner, A., and Massie, A.
  • Journal Title: J. Neuroinflam Volume: 14 Issue: 1 Pages: 9-9
  • DOI: 10.1186/s12974-016-0787-0
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] ヒト線維肉腫由来細胞の浸潤能におけるシスチン・グルタミン酸輸送体の役割 (2019)
  • Author(s): 土門美緒、長谷川駿、佐藤茉美、坂内四郎、フィーダーレ レジーナ、コンラッド マルクス、佐藤英世
  • Organizer: 第42回日本分子生物学会
• [Presentation] xCT遺伝子欠損マウスメラノーマ細胞の細胞死解析と腫瘍増殖能の評価 (2018)
  • Author(s): 佐藤茉美、鈴木亜美、久住亮介、小沼邦重、尾崎充彦、坂内四郎、岡田 太、Marcus Conrad、佐藤英世
  • Organizer: 第91回日本生化学会大会
• [Presentation] xCT遺伝子欠損マクロファージの生存を可能にする分子機構の解明 (2018)
  • Author(s): 小林翔、本間拓二郎、奥村宜明、佐藤英世、高尾敏文、藤井順逸
  • Organizer: 第91回日本生化学会大会
• [Presentation] マウス敗血症モデルにおけるシスチントランスポーターの影響 (2018)
  • Author(s): 風間絢香、大谷真志、茂呂和世、佐藤英世、渡辺直子
  • Organizer: 第41回日本分子生物学会大会
• [Presentation] The cystine/glutamate antiporter is essential for maintaining the highly metastatic potential of B16F10 skin melanoma cells. (2018)
  • Author(s): Sato, M., Onuma, K., Silva, M.S.C.D., Kusumi, R., Osaki, M., Feederle, R., Bannai, S., Conrad, M., Okada, F., and Sato, H.
  • Organizer: The 2018 Cold Spring Harbor Asia Conference: IRON, REACTIVE OXYGEN SPECIES & FERROPTOSIS IN LIFE, DEATH & DISEASE.
  • Int'l Joint Research
• [Presentation] シスチン/グルタミン酸輸送体は細胞内グルタチオンの維持を通じてがん細胞の遊走・浸潤・転移に寄与する (2017)
  • Author(s): 佐藤茉美、鈴木亜美、小沼邦重、尾崎充彦、坂内四郎、岡田太、佐藤英世
  • Organizer: ConBio2017生命科学系合同年次大会（第90回日本生化学会、第40回日本分子生物学会）
• [Presentation] ヒト由来骨肉腫細胞の浸潤能とグルタチオン合成系との関連性 (2017)
  • Author(s): 久住亮介、鈴木悠、小沼邦重、尾崎充彦、坂内四郎、岡田太、佐藤英世
  • Organizer: ConBio2017生命科学系合同年次大会（第90回日本生化学会、第40回日本分子生物学会）
• [Presentation] シスチントランスポーター・xCT欠損マウスは雄性生殖能が低下する (2017)
  • Author(s): 本間拓二郎、浜島真司、小林翔、倉橋敏裕、渡辺連、木村直子、佐藤英世、藤井順逸
  • Organizer: ConBio2017生命科学系合同年次大会（第90回日本生化学会、第40回日本分子生物学会）