Elucidating the role of glutamate in xCT-expressing cancer cells

• Project/Area Number: 18K15215
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 50010:Tumor biology-related
• Research Institution: Kyushu University
• Principal Investigator: Tsuchihashi Kenji 九州大学, 大学病院, 助教 (20773675)
• Project Period (FY): 2018-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥3,120,000 (Direct Cost: ¥2,400,000、Indirect Cost: ¥720,000); 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)
• Keywords: xCT / EGFR / Glutamate / Glioma / グルタミン酸受容体 / NMDA受容体 / 上皮成長因子受容体 / 脳腫瘍 / グルタミン酸 / NMDA / がん幹細胞

Outline of Final Research Achievements

We previously showed that EGFR-expressing glioma cells highly express xCT which is cystine-glutamate antiporter. In the present project, we showed released glutamate promotes the migration of glioma cells through the activaton of NMDA
type glutamate receptor. In response to EGF stimulation, EGFR phosphorylated the COOH-terminal domain of GluN2B, the subunit of NMDA type glutamate receptor, and thereby enhanced glutamate-NMDAR signaling and consequent cell migration in EGFR-overexpressing glioma cells.The administration of sulfasalazine and NMDA type glutamate inhibitor, MK-801, also synergistically suppressed the growth of subcutaneous tumors formed by EGFR-overexpressing glioma cells. Furthermore, shRNA-mediated knockdown of xCT and GluN2B cooperatively prolonged the survival of mice injected intracerebrally with such glioma cells. Our findings thus show the efficacy of combinatory treatment by xCT and glutamate receptor inhibtion for EGFR-xCT expressing glioma cells.

Academic Significance and Societal Importance of the Research Achievements

xCTはアミノ酸トランスポーターの一つであり、様々ながん種や、さらにその中で治療抵抗性が高いとされるがん幹細胞という一部の集団で発現が高いことが報告されている。xCT発現がん細胞に対する治療開発が期待されている。本研究では、xCTを介し放出されたグルタミン酸ががん細胞上のグルタミン酸受容体に結合し、がんの悪性化を促進するを明らかにした。その中でEGFRという別の分子がグルタミン酸受容体を活性化することを初めて明らかにした。xCT阻害に加え、グルタミン酸受容体阻害を行うことで、抗腫瘍効果が高まることを明らかにした。本研究は、xCTとグルタミン酸受容体阻害の併用という新しい治療戦略を打ち出した。

Research Products

• [Journal Article] Endothelial-Mesenchymal Transition Drives Expression of CD44 Variant and xCT in Pulmonary Hypertension (2019)
  • Author(s): Isobe Sarasa、Kataoka Masaharu、Endo Jin、Moriyama Hidenori、Okazaki Shogo、Tsuchihashi Kenji、Katsumata Yoshinori、Yamamoto Tsunehisa、Shirakawa Kohsuke、Yoshida Naohiro、Shimoda Masayuki、Chiba Tomohiro、Masuko Takashi、Hakamata Yoji、Kobayashi Eiji、Saya Hideyuki、Fukuda Keiichi、Sano Motoaki
  • Journal Title: American Journal of Respiratory Cell and Molecular Biology Volume: Volume61,Issue3 Issue: 3 Pages: 367-379
  • DOI: 10.1165/rcmb.2018-0231oc
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] EGFR promotes glioma progression by regulating xCT and GluN2B-containing NMDA receptor signaling. (2018)
  • Author(s): Suina K, Tsuchihashi K, Yamasaki J, Kamenori S, Shintani S, Hirata Y, Okazaki S, Sampetrean O, Baba E, Akashi K, Takahashi F, Takahashi K, Saya H, Nagano O.
  • Journal Title: Cancer Science Volume: 109 Issue: 12 Pages: 3874-3882
  • DOI: 10.1111/cas.13826
  • Peer Reviewed / Open Access