Stemness as a target for anti-cancer drug development

• Project/Area Number: 20H03151
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 42020:Veterinary medical science-related
• Research Institution: Yamaguchi University
• Principal Investigator: Ohama Takashi 山口大学, 共同獣医学部, 准教授 (50579018)
• Co-Investigator(Kenkyū-buntansha): 大松 勉 東京農工大学, 農学部, 准教授 (60455392)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥17,680,000 (Direct Cost: ¥13,600,000、Indirect Cost: ¥4,080,000); Fiscal Year 2022: ¥5,980,000 (Direct Cost: ¥4,600,000、Indirect Cost: ¥1,380,000); Fiscal Year 2021: ¥5,850,000 (Direct Cost: ¥4,500,000、Indirect Cost: ¥1,350,000); Fiscal Year 2020: ¥5,850,000 (Direct Cost: ¥4,500,000、Indirect Cost: ¥1,350,000)
• Keywords: Protein Phosphatase 2A / がん幹細胞 / がん幹細胞性 / Protein phosphatase 2A / SET / がん

Outline of Research at the Start

近年、がんの再発・転移・治療抵抗性の原因としてがん幹細胞が注目されているが、幹細胞性維持の分子機構が十分に解明されておらず、がん幹細胞を標的とした創薬は実現していない。本研究の目的は、「がん幹細胞性」維持機構への理解を深めることで、創薬実現への足がかりにすることである。具体的には、申請者が昨年報告したがん増悪因子SETがProtein Phosphatase 2A（PP2A）の活性を阻害することにより幹細胞性が維持される分子機構の詳細を解明するとともに、PP2AとSETのタンパク質間結合（PPI）を標的とした化合物の抗がん剤としての適応の可能性を明らかにする。

Outline of Final Research Achievements

Recently, the importance of "cancer stem cells" as a cause of cancer recurrence, metastasis, and resistance to treatment has become clear, and drug discovery targeting these cells has attracted attention. In this study, we focused on the protein phosphatase PP2A and its inhibitor protein SET to elucidate the molecular mechanisms by which cancer stem cells maintain their stemness, and to analyze the possibility of novel drug discovery strategies targeting the protein-protein interaction between SET and PP2A. As a result, they elucidated the molecular mechanism by which SET expression is upregulated in cancer and identified small molecule compounds that dissociate the binding between SET and PP2A. A series of research results were published in three original papers during the project period, and two more research projects are currently in preparation for publication.

Academic Significance and Societal Importance of the Research Achievements

本研究は、がん幹細胞の幹細胞性維持機構を脱リン酸化酵素の活性阻害機構の解明を通して明らかにするものである。リン酸化酵素キナーゼと比較して脱リン酸化酵素ホスファターゼの研究は遅れており、キナーゼ阻害剤は分子標的抗がん剤として幅広く用いられているが、同じベクトルの作用を示すホスファターゼ活性化剤は、未だに上市されていない。ホスファターゼ活性化薬は、キナーゼ阻害剤との相加・相乗効果や、キナーゼ阻害剤に抵抗性または耐性を獲得した症例に対する効果が期待できる。

Research Products

• [Journal Article] The protein level of the tumour-promoting factor SET is regulated by cell density (2022)
  • Author(s): Kohyanagi Naoki、Kitamura Nao、Tanaka Keiko、Mizuno Takuya、Fujiwara Nobuyuki、Ohama Takashi、Sato Koichi
  • Journal Title: The Journal of Biochemistry Volume: 171 Issue: 3 Pages: 295-303
  • DOI: 10.1093/jb/mvab125
  • Peer Reviewed
• [Journal Article] Autophagy regulates levels of tumor suppressor enzyme protein phosphatase 6. (2020)
  • Author(s): Nobuyuki Fujiwara, Shusaku Shibutani, Yusuke Sakai, Toshio Watanabe, Issei Kitabayashi, Hiroko Oshima, Masanobu Oshima, Hisashi Hoshida, Rinji Akada, Tatsuya Usui, Takashi Ohama*, Koichi Sato.
  • Journal Title: Cancer Science Volume: 111 Issue: 12 Pages: 4371-4380
  • DOI: 10.1111/cas.14662
  • Peer Reviewed / Open Access
• [Journal Article] Established fibrous peritoneal metastasis in an immunocompetent mouse model similar to clinical immune microenvironment of gastric cancer (2020)
  • Author(s): Daisuke Fujimori, Jun Kinoshita, Takahisa Yamaguchi, Yusuke Nakamura, Katsuya Gunjigake, Takashi Ohama, Koichi Sato, Masami Yamamoto, Tetsuya Tsukamoto, Sachiyo Nomura, Tetsuo Ohta, Sachio Fushida
  • Journal Title: BMC Cancer Volume: 20 Issue: 1 Pages: 1014-1014
  • DOI: 10.1186/s12885-020-07477-x
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Involvement of PP2A methylation in the adipogenic differentiation of bone marrow-derived mesenchymal stem cell (2020)
  • Author(s): Ikeda Shunta、Tsuji Shunya、Ohama Takashi、Sato Koichi
  • Journal Title: The Journal of Biochemistry Volume: 168 Issue: 6 Pages: 643-650
  • DOI: 10.1093/jb/mvaa077
  • NAID: 40022458849
  • Peer Reviewed
• [Journal Article] Perphenazine exerts antitumor effects on HUT78 cells through Akt dephosphorylation by protein phosphatase?2A (2020)
  • Author(s): Tsuji Shunya、Kohyanagi Naoki、Mizuno Takuya、Ohama Takashi、Sato Koichi
  • Journal Title: Oncology Letters Volume: 21(2) Issue: 2 Pages: 113-113
  • DOI: 10.3892/ol.2020.12374
  • Peer Reviewed
• [Presentation] High cell density enhances the protein expression level of SET (2022)
  • Author(s): Kohyanagi N, Kitamura N, Tanaka K, Mizuno T, Fujiwara N, Ohama T, Sato K
  • Organizer: The 6th International Symposium Association of Japan-Indonesia Veterinary Education 2022
  • Int'l Joint Research
• [Presentation] 腫瘍促進因子SETのタンパク質発現レベルは細胞密度により制御される (2022)
  • Author(s): 幸柳尚規、北村菜央、田中慶子、藤原信行、大浜剛、佐藤晃一
  • Organizer: 第95回日本薬理学会年会
• [Presentation] SET/I2PP2A protein is up-regulated at high cell density (2021)
  • Author(s): Kohyanagi N, Kitamura N, Fujiwara N, Ohama T, Sato K
  • Organizer: The 23rd Korea-Japan Joint Seminar on Pharmacology (23rd KJJSP)
  • Int'l Joint Research
• [Presentation] 細胞密度の上昇によりがん促進因子SETとSETBP1のタンパク質発現量の増加する (2021)
  • Author(s): 幸柳尚規、北村菜央、田中慶子、藤原信行、大浜剛、佐藤晃一
  • Organizer: 第94回日本生化学会大会
• [Presentation] The role of PP2A inhibitory protein SET in cancer and its possibility as a drug target. (2020)
  • Author(s): 大浜剛
  • Organizer: 第43回日本分子生物学会年会
• [Presentation] The dual role of PME-1: PP2A inhibitory protein and methyl-esterase (2020)
  • Author(s): Takashi Ohama
  • Organizer: The 14th International Conference on Protein Phosphatases
  • Int'l Joint Research / Invited