Elucidation of the mechanism of antitumor effect in inhibition of GGCT expression using integrated omics analysis

• Project/Area Number: 17K11131
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Urology
• Research Institution: Shiga University of Medical Science
• Principal Investigator: Kubota Shigehisa 滋賀医科大学, 医学部, 医員 (80759118)
• Co-Investigator(Kenkyū-buntansha): 礒野 高敬 滋賀医科大学, 実験実習支援センター, 准教授 (20176259) ; 影山 進 滋賀医科大学, 医学部, 講師 (50378452) ; 吉田 哲也 滋賀医科大学, 医学部, 助教 (60510310) ; 河内 明宏 滋賀医科大学, 医学部, 教授 (90240952)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2019: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2018: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2017: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000)
• Keywords: γ-グルタミルシクロトランスフェラーぜ / トランスクリプトーム解析 / メタボローム解析 / 抗腫瘍メカニズム / 癌関連タンパク / γ-グルタミルシクロトランスフェラーゼ / 細胞周期関連遺伝子 / 増殖抑制機構

Outline of Final Research Achievements

We performed omics analysis to elucidate the mechanism of anti-tumor effect in inhibiting the cancer growth-related protein GGCT. Transcriptome analysis using breast cancer-derived MCF-7 revealed significant changes of expression level of cell cycle-related genes. In the network of cell cycle, GGCT depletion induced up-regulation of CDK inhibitors (p15 and p21), and simultaneous knockdown of p15 and/or p21 recovered the cell cycle arrest, and rescued the subsequent growth inhibition. Further analysis revealed the activation of TGFβ-SMAD signaling pathway associated with induction of CDK inhibitors, was one of anti-tumor mechanisms on GGCT depletion.

Academic Significance and Societal Importance of the Research Achievements

GGCTは発現阻害により癌特異的に増殖抑制効果を示す有望な治療標的であり，種々の癌における新規治療への応用が期待されている．本研究の結果により，GGCT阻害によりTGFβ-SMAD signaling pathway が活性化され，CDK inhibitorの誘導を介した細胞周期停止が起こることが明らかになった．この機序は，従来の抗癌剤や分子標的薬が提唱するアポトーシス細胞死とは異なるメカニズムであり，既存治療抵抗例への治療効果や既存治療への併用による治療効果の向上が期待される．GGCTを標的とする新規治療の開発に必須である作用機序の一端を解明し得た点が，非常に有意義であると考えられる．

Research Products

• [Journal Article] Blockade of γ-Glutamylcyclotransferase Enhances Docetaxel Growth Inhibition of Prostate Cancer Cells (2019)
  • Author(s): TAKAGI HIROKO、II HIROMI、KAGEYAMA SUSUMU、HANADA EIKI、TANIGUCHI KEIKO、YOSHIYA TAKU、CHANO TOKUHIRO、KAWAUCHI AKIHIRO、NAKATA SUSUMU
  • Journal Title: Anticancer Research Volume: 39 Issue: 9 Pages: 4811-4816
  • DOI: 10.21873/anticanres.13666
  • Peer Reviewed / Open Access
• [Journal Article] Depletion of gamma-glutamylcyclotransferase inhibits cancer cell growth by activating the AMPK?FOXO3a?p21 axis (2019)
  • Author(s): Taniguchi Keiko、Ii Hiromi、Kageyama Susumu、Takagi Hiroko、Chano Tokuhiro、Kawauchi Akihiro、Nakata Susumu
  • Journal Title: Biochemical and Biophysical Research Communications Volume: 517 Issue: 2 Pages: 238-243
  • DOI: 10.1016/j.bbrc.2019.07.049
  • Peer Reviewed / Open Access
• [Journal Article] Pro-GA, a Novel Inhibitor of γ-Glutamylcyclotransferase, Suppresses Human Bladder Cancer Cell Growth (2019)
  • Author(s): HANADA EIKI、KAGEYAMA SUSUMU、MURAI RYOSUKE、KUBOTA SHIGEHISA、II HIROMI、NAKATA SUSUMU、KITA HIROKO、KAWAUCHI AKIHIRO、CHANO TOKUHIRO
  • Journal Title: Anticancer Research Volume: 39 Issue: 4 Pages: 1893-1898
  • DOI: 10.21873/anticanres.13297
  • Peer Reviewed / Open Access
• [Presentation] GGCTを治療標的とした尿路上皮癌治療の基礎的検討 (2019)
  • Author(s): 影山 進, 窪田 成寿, 村井 亮介, 吉田 哲也, 成田 充弘, 茶野 徳宏, 河内 明宏
  • Organizer: 日本泌尿器科学会総会