Exploring the characteristics of tumor-promoting glycometabolism enhanced by GSK3beta toward application to cancer therapy.

• Project/Area Number: 19K07710
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 50020:Tumor diagnostics and therapeutics-related
• Research Institution: Kanazawa University
• Principal Investigator: Domoto Takahiro 金沢大学, がん進展制御研究所, 助教 (80635540)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2021: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2020: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2019: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: 分子標的治療 / がん代謝 / GSK3β / オートファジー / 大腸がん / 乳酸

Outline of Research at the Start

申請者らは、がん細胞で異常な発現と活性を示すGSK3βのがん促進作用を大腸がんや難治・希少がんで発見し、その阻害による治療効果を実証してきた。本研究では、GSK3βが解糖系を亢進することで大腸がん細胞の乳酸を介するオートファジーを駆動して、がんの増殖や悪性化を促進しているのかを明らかにするため、GSK3β誘導性の糖代謝特性に着目して検討する。そして、がん細胞における解糖系亢進と細胞の生存を支えるオートファジーの両者を一連の経路として認識し、GSK3β阻害によるがん治療作用をがん細胞の栄養獲得機構の視点から解明する。

Outline of Final Research Achievements

We investigated the tumor promoting role of GSK3β by focusing on nutrient acquisition mechanism in cancer cells, and clarified the effect of GSK3β on lactate production and induction of autophagy in colon cancer. Analysis of the efficacy of combined treatment with GSK3β inhibitor and autophagy inhibitor for cell growth and of its mechanism suggest that nutrient acquisition mechanism may be as a promising therapeutic target for cancer treatment.

Academic Significance and Societal Importance of the Research Achievements

がんは解糖系優位な代謝への依存とともに、オートファジーをエネルギー源として利用している。GSK3βが解糖系とオートファジーを一連の経路として統合的に制御しているというメカニズムが示されることによって、がん特有の代謝を一括で標的にするという独創的な治療法の科学的基盤になることが期待される。また、がん特有の代謝経路を広く理解することにより、がんの病態解明と新たな治療法の開発につながることはもとより、代謝異常による細胞現象への理解や他の疾患に対する治療法開発の応用に波及する可能性がある。

Research Products

• [Journal Article] Discovery of a Novel Aminocyclopropenone Compound That Inhibits BRD4-Driven Nucleoporin NUP210 Expression and Attenuates Colorectal Cancer Growth (2022)
  • Author(s): Kondo Hiroya、Mishiro Kenji、Iwashima Yuki、Qiu Yujia、Kobayashi Akiko、Lim Keesiang、Domoto Takahiro、Minamoto Toshinari、Ogawa Kazuma、Kunishima Munetaka、Hazawa Masaharu、Wong Richard W.
  • Journal Title: Cells Volume: 11 Issue: 3 Pages: 317-317
  • DOI: 10.3390/cells11030317
  • Peer Reviewed / Open Access
• [Journal Article] Glycogen synthase kinase 3β in cancer biology and treatment. (2020)
  • Author(s): Takahiro Domoto, Masahiro Uehara, Dilireba Bolidong, Toshinari Minamoto
  • Journal Title: Cells Volume: 9 Issue: 6 Pages: 1388-1388
  • DOI: 10.3390/cells9061388
  • Peer Reviewed / Open Access
• [Journal Article] Potential therapeutic effect of targeting glycogen synthase kinase 3β in esophageal squamous cell carcinoma (2020)
  • Author(s): Dilireba Bolidong, Takahiro Domoto, Masahiro Uehara, Hemragul Sabit, Tomoyuki Okumura, Yoshio Endo, Mitsutoshi Nakada, Itasu Ninomiya, Tomoharu Miyashita, Richard W Wong, Toshinari Minamoto
  • Journal Title: Scientific Reports Volume: 10 Issue: 1 Pages: 11807-11807
  • DOI: 10.1038/s41598-020-68713-9
  • Peer Reviewed / Open Access
• [Journal Article] Glycogen synthase kinase-3β participates in acquired resistance to gemcitabine in pancreatic cancer (2020)
  • Author(s): Masahiro Uehara, Takahiro Domoto, Satoshi Takenaka, Dilireba Bolidong, Osamu Takeuchi, Tomoharu Miyashita, Toshinari Minamoto
  • Journal Title: Cancer Science Volume: 111 Issue: 12 Pages: 4405-4416
  • DOI: 10.1111/cas.14668
  • Peer Reviewed / Open Access
• [Journal Article] Identification of GSK3β inhibitor kenpaullone as a temozolomide enhancer against glioblastoma (2019)
  • Author(s): Kitabayashi Tomohiro、Dong Yu、Furuta Takuya、Sabit Hemragul、Jiapaer Shabierjiang、Zhang Jiakang、Zhang Guangtao、Hayashi Yasuhiko、Kobayashi Masahiko、Domoto Takahiro、Minamoto Toshinari、Hirao Atsushi、Nakada Mitsutoshi
  • Journal Title: Scientific Reports Volume: 9 Issue: 1 Pages: 10049-10049
  • DOI: 10.1038/s41598-019-46454-8
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Glycogen synthase kinase 3β as a potential therapeutic target in synovial sarcoma and fibrosarcoma (2019)
  • Author(s): Abe Kensaku、Yamamoto Norio、Domoto Takahiro、Bolidong Dilireba、Hayashi Katsuhiro、Takeuchi Akihiko、Miwa Shinji、Igarashi Kentaro、Inatani Hiroyuki、Aoki Yu、Higuchi Takashi、Taniguchi Yuta、Yonezawa Hirotaka、Araki Yoshihiro、Aiba Hisaki、Minamoto Toshinari、Tsuchiya Hiroyuki
  • Journal Title: Cancer Science Volume: 111 Issue: 2 Pages: 429-440
  • DOI: 10.1111/cas.14271
  • Peer Reviewed / Open Access
• [Presentation] Glycogen synthase kinase (GSK)3β renders pancreatic cancer acquiring resistance to gemcitabine via STAT3 activation (2021)
  • Author(s): Takahiro Domoto, Satoshi Takenaka, Masahiro Uehara, Dilireba Bolidong, Tatsuhiko Furukawa, Tomoharu Miyashita, Toshinari Minamoto
  • Organizer: 第80回日本癌学会学術総会
• [Presentation] GSK3β interconnects the malignant properties in therapy-resistant pancreatic cancer (2021)
  • Author(s): Takahiro Domoto, Masahiro Uehara, Satoshi Takenaka, Dilireba Bolidong, Tatsuhiko Furukawa, Osamu Takeuchi, Tomoharu Miyashita, Toshinari Minamoto
  • Organizer: The 10th International Conference of the International Society of Gastroenterological Carcinogenesis (ISGC)
  • Int'l Joint Research
• [Presentation] Glycogen synthase kinase (GSK) 3β participates in acquired resistance to gemcitabine in pancreatic cancer (2021)
  • Author(s): Masahiro Uehara, Takahiro Domoto, Satoshi Takenaka, Dilireba Bolidong, Osamu Takeuchi, Tomoharu Miyashita, Toshinari Minamoto.
  • Organizer: The 10th International Conference of the International Society of Gastroenterological Carcinogenesis (ISGC)
  • Int'l Joint Research
• [Presentation] Potential therapeutic effect of targeting glycogen syntase kinase (GSK)3β in esophageal squamous cell carcinoma (ESCC) (2021)
  • Author(s): Dilireba Bolidong, Takahiro Domoto, Masahiro Uehara, Hemragul Sabit, Tomoyuki Okumura, Yoshio Endo, Mitutoshi Nakada, Tomoharu Miyashita, Richard W. Wong, Toshinari Minamoto
  • Organizer: The 10th International Conference of the International Society of Gastroenterological Carcinogenesis (ISGC)
  • Int'l Joint Research
• [Presentation] Role of GSK3β in malignant progression of pancreatic cancer associated with gemcitabine resistance. (2020)
  • Author(s): 堂本貴寛, 宮下知治, Bolidong Dilireba, 上原将大, 竹中 哲, 竹内 修, 太田哲生, 源 利成
  • Organizer: 第29回日本がん転移学会学術集会・総会
• [Presentation] GSK3β interconnects cancer stemness and invasive capacity in pancreatic cancer with acquired resistance to gemcitabine (2020)
  • Author(s): Takahiro Domoto, Tomoharu Miyashita, Satoshi Takenaka, Masahiro Uehara, Dilireba Bolidong, Tetsuo Ohta, Toshinari Minamoto
  • Organizer: 第79回日本癌学会学術総会
• [Presentation] Glycogen synthase kinase (GSK)-3β as a new target to overcome acquired resistance to gemcitabine in pancreatic cancer (2020)
  • Author(s): Masahiro Uehara, Takahiro Domoto, Satoshi Takenaka, Diliraba Bolidong, Takeo Shimasaki, Tomoharu Miyashita, Tetsuo Ohta, Toshinari Minamoto
  • Organizer: 第79回日本癌学会学術総会
• [Presentation] Dilireba Bolidong, Takahiro Domoto, Masahiro Uehara, Tomoyuki Okumura, Yoshio Endo, Mitsutoshi Nakada, Itasu Ninomiya, Tomoharu Miyashita, Richard W. Wong, Toshinari Minamoto (2020)
  • Author(s): Potential therapeutic effect of targeting glycogen synthase kinase 3β in esophageal squamous cell carcinoma
  • Organizer: 第31回日本消化器癌発生学会総会
• [Presentation] GSK3βは膵がんのゲムシタビン耐性獲得に寄与する (2020)
  • Author(s): 上原将大，堂本貴寛，竹中 哲，ディリラバ ボリドン，竹内 修，宮下知治，源 利成
  • Organizer: 第31回日本消化器癌発生学会総会
• [Remarks] 金沢大学がん進展制御研究所腫瘍制御研究分野ホームページ
  • URL: http://ganken.cri.kanazawa-u.ac.jp/shuyoseigyo/index.html
• [Remarks] 金沢大学 がん進展制御研究所 腫瘍制御研究分野 ホームページ
  • URL: http://ganken.cri.kanazawa-u.ac.jp/shuyoseigyo/index.html