Development of therapeutic strategry breaking resistance to oxidative stress in glioma

• Project/Area Number: 16K18454
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Tumor therapeutics
• Research Institution: Kyushu University
• Principal Investigator: Tsuchihashi Kenji 九州大学, 大学病院, 助教 (20773675)
• Research Collaborator: OKAZAKI Shogo ; OHMURA Mitsuyo ; ISHIKAWA Miyuki ; SAMPETREAN. Oltea ; ONISHI Nobuyuki ; WAKIMOTO Hiroaki ; YOSHIKAWA Momoko ; SEISHIMA Ryo ; IWASAKI Yoshimi ; MORIKAWA Takayuki ; ABE Shinya ; TAKAO Ayumi ; SHIMIZU Misato ; MASUKO Takashi ; NAGANE Motoo ; Frank Furnari ; AKIYAMA Tetsu ; SUEMATSU Makoto ; BABA Eishi ; AKASHI Koichi ; SAYA Hideyuki ; NAGANO Osamu
• Project Period (FY): 2016-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥3,640,000 (Direct Cost: ¥2,800,000、Indirect Cost: ¥840,000); Fiscal Year 2017: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2016: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: 脳腫瘍 / xCT / 酸化ストレス / グルタチオン / グルタミン酸 / EGFR / 還元型グルタチオン

Outline of Final Research Achievements

Malignant glioma such as glioblastoma is a cancer still difficult to treat. xCT functions as a plasma membrane antiporter for the uptake of extracellular cystine in exchange for intracellular glutamate. Epidermal growth factor receptor (EGFR) interacts with xCT and thereby promotes its cell surface expression and function in human glioma cells. EGFR-expressing glioma cells manifested both enhanced antioxidant capacity as a result of increased cystine uptake as well as increased extracellular glutamate which promotes glioma matrix invasion. Targeted inhibition of xCT suppressed the EGFR-dependent enhancement of antioxidant capacity in glioma cells as well as tumor growth and invasiveness. Our findings propose that xCT is a promising therapeutic target in EGFR-overexpressing malignant glioma.

Research Products

• [Int'l Joint Research] Harvard Medical School/UC San Diego(米国)
• [Journal Article] Programmed death-ligand 1 expression is associated with fibrosarcomatous transformation of dermatofibrosarcoma protuberans (2017)
  • Author(s): K Tsuchihashi, H Kusaba, Y Yamada, Y Okumura, H Kumagai, M Komoda, K Uchino, T Yoshihiro, N Tsuruta, F Hanamura, K Inadomi, M Ito, K Sagara, M Nakano, K Nio, K Kohashi, S Arita, H Ariyama, R Tominaga, Y Oda, K Akashi, E Baba
  • Journal Title: Molecular and Clinical Oncology Volume: 印刷中 Issue: 5 Pages: 665-668
  • DOI: 10.3892/mco.2017.1197
  • Peer Reviewed
• [Journal Article] The EGF receptor promotes the malignant potential of glioma by regulating amino acid transport system xc(-) (2016)
  • Author(s): Tsuchihashi K, Okazaki S, Ohmura M, Ishikawa M, Sampetrean O, Onishi N, Wakimoto H, Yoshikawa M, Seishima R, Iwasaki Y, Morikawa T, Abe S, Takao A, Shimizu M, Masuko T, Nagane M, Furnari FB, Akiyama T, Suematsu M, Baba E, Akashi K, Saya H, Nagano O.
  • Journal Title: Cancer Research Volume: in press Issue: 10 Pages: 2954-2963
  • DOI: 10.1158/0008-5472.can-15-2121
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] Glutaminolytic metabolism on CD44vhigh undifferentiated HNSCC cells enhances xCT dependency (2017)
  • Author(s): 岡崎 章悟、新谷 昴、土橋 賢司、佐谷 秀行、永野 修
  • Organizer: 第76回日本癌学会学術集会
• [Presentation] The EGF receptor promotes the malignant potential of glioma by regulating amino acid transport system xc(-) (2016)
  • Author(s): 土橋賢司、永野修、岡崎章悟、大村光代、サンペトラオルテア、吉川桃子、清島亮、大西伸幸、益子高、末松誠、馬場英司、赤司浩一、佐谷秀行
  • Organizer: 第75回日本癌学会学術総会
  • Place of Presentation: 横浜
  • Year and Date: 2016-10-09