Elucidation of induction of ferroptosis and inhibition of tumor growth caused by suppressing cystine transporter xCT

• Project/Area Number: 16H06648
• Research Category: Grant-in-Aid for Research Activity Start-up
• Allocation Type: Single-year Grants
• Research Field: Pathological medical chemistry
• Research Institution: Yamagata University
• Principal Investigator: Kobayashi Sho 山形大学, 大学院医学系研究科, 助教 (10779490)
• Research Collaborator: Fujii Junichi 山形大学, 大学院医学系研究科, 教授 (00222258) ; Homma Takujiro 山形大学, 大学院医学系研究科, 助教 (70743566)
• Project Period (FY): 2016-08-26 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥2,990,000 (Direct Cost: ¥2,300,000、Indirect Cost: ¥690,000); Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2016: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: グルタチオン / システイン / xCT / ferroptosis / マクロファージ / オフタルミン酸 / プロテオミクス / ｘＣＴ / Ｆｅｒｒｏｐｔｏｓｉｓ / 癌 / シスチン輸送体 / セレン

Outline of Final Research Achievements

We established a method for simultaneous measurement of low molecular thiols and ophthalmic acid, which is an oxidative stress marker, and found an increase in ophthalmic acid level but a decrease in glutathione level in plasma and liver of fasting mice. Analyses of macrophages from xCT-deficient mice by using this method indicated that they were severe deficiency in cysteine and glutathione but could survive for several days under conditions with high oxidative stress. These results suggest that macrophages have unique glutathione-independent survival system. Meantime, nitric oxide production in xCT-deficient macrophages was significantly decreased compared to that in WT cells.

Research Products

• [Int'l Joint Research] Helmholtz Zentrum Muenchen(ドイツ)
• [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 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] Increased ophthalmic acid production is supported by amino acid catabolism under fasting conditions in mice. (2017)
  • Author(s): Sho Kobayashi, Jaeyong Lee, Toshifumi Takao, Junichi Fujii.
  • Journal Title: Biochemical and Biophysical Research Communications Volume: 491 Issue: 3 Pages: 649-655
  • DOI: 10.1016/j.bbrc.2017.07.149
  • Peer Reviewed
• [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
• [Presentation] マクロファージの酸化ストレス防御とNO産生におけるシスチン・グルタミン酸トランスポーターの役割 (2017)
  • Author(s): 小林翔、浜島真司、本間拓二郎、藤井順逸、佐藤英世
  • Organizer: 第17回日本NO学会
• [Presentation] xCT欠損によりグルタチオン・レドックスバランスに障害のあるマクロファージの細胞培養系における性質 (2017)
  • Author(s): 小林翔、浜島真司、本間拓二郎、佐藤英世、藤井順逸
  • Organizer: 日本生化学会東北支部第83回例会
• [Presentation] Macrophages from xCT-deficient mice survive under low cysteine/glutathione redox conditions with high oxidative stress. (2017)
  • Author(s): Sho Kobayashi , Shinji Hamashima, Takujiro Homma, Junichi Fujii, Hideyo Sato
  • Organizer: OCC World Congress 2017 and Annual SFRR-E Conference
  • Int'l Joint Research
• [Presentation] 絶食によるアミノ酸代謝の亢進はオフタルミン酸合成を促進する (2017)
  • Author(s): 小林翔、李在勇、高尾敏文、藤井順逸
  • Organizer: 2017年度生命科学系学会合同年次大会（ConBio2017）
• [Presentation] 肝臓へのシステイン供給におけるxCTとTranssulfuration経路の役割 (2016)
  • Author(s): 小林翔、姜恩實、李在勇、本間拓二郎、倉橋敏裕、徐漢克、佐藤英世、藤井順逸
  • Organizer: 第69回日本酸化ストレス学会学術集会
  • Place of Presentation: 仙台国際センター会議棟、仙台市、宮城県
  • Year and Date: 2016-08-30
• [Remarks] 山形大学大学院 医学系研究科 生命環境医化学専攻 生化学・分子生物学講座
  • URL: http://www.id.yamagata-u.ac.jp/BiochemII/b2.html