Anti-tumor activity of potent PDK4 inhibitors from plants for KRAS-mutated intractable cancers
| Project/Area Number |
19K07480
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Multi-year Fund |
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| Section | 一般 |
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| Review Section |
Basic Section 49030:Experimental pathology-related
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| Research Institution | Shiga University of Medical Science |
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Principal Investigator |
Inoue Hirokazu 滋賀医科大学, 医学部, 非常勤講師 (30176440)
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| Project Period (FY) |
2019-04-01 – 2022-03-31
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| Project Status |
Completed (Fiscal Year 2021)
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| Budget Amount *help |
¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000)
Fiscal Year 2021: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000)
Fiscal Year 2020: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2019: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
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| Keywords | Cryptotanshinone / PDK4 / K-Ras / 膵臓癌 / 脂質代謝 / 活性酸素 / PDK４阻害剤 / KRAS / エネルギー代謝 / 抗癌剤 / PDK４ / 癌幹細胞 |
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| Outline of Research at the Start |
本申請では、解糖-呼吸系調節因子PDK4を分子標的とする新しい低分子化合物KIS37(Cryptotanshinone)に着目して、その代謝調節作用と抗腫瘍活性をKRAS遺伝子の変異を持つヒト膵臓癌および大腸癌細胞株を用いて解析する。またヒト膵臓癌および大腸癌患者由来の腫瘍組織、 さらにin vivoのマウス同所性膵臓腫瘍モデル実験系、膵臓腫瘍の転移浸潤実験系などを用いて前臨床的実験を行い、難治性癌に対する新たな治療法を樹立する。
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| Outline of Final Research Achievements |
Pyruvate dehydrogenase kinase 4 (PDK4) is an important regulator of energy metabolism. Knockdown of PDK4 by specific siRNA suppressed the expression of KRAS and the proliferation of cancer cells. We found a novel small molecule, cryptotanshinone (CPT), which inhibits PDK4 activity, suppressed the 3D-spheroid formation and tumorigenesis of KRAS-activated human pancreatic cancer cells. In this study, we examined the molecular mechanism of tumor suppression by CPT in human pancreatic cell lines. CPT treatment decreased glutamine and lipid metabolism, and increased ROS production in a pancreatic cancer cell line MIAPaCa-2 containing mutant KRAS. By knockdown experiments of activated K-Ras, we demonstrated that CPT suppresses tumorigenesis by inhibiting lipid metabolism and promoting ROS production in a mutant KRAS-dependent manner. This PDK4 inhibitor represents a novel therapeutic drug for KRAS-driven intractable cancers by altering cell metabolism.
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| Academic Significance and Societal Importance of the Research Achievements |
癌細胞の代謝を標的にした新たな抗癌剤の開発が始まっているが臨床レベルで標準治療として使用できる薬剤はまだ出てきていない。CPTはその活性のひとつとして活性化Ras蛋白の発現抑制があるのでRasが活性化した膵臓癌などの難治癌に対する有効な治療薬になることが考えられる。KRAS遺伝子変異が90%を占める膵臓癌は癌の中でも最も10年生存率が低い難治性癌であり、有効で副作用の少ない新規治療薬は必須である。K-Rasは解糖系、グルタミン代謝、脂質代謝系などの上流で働きエネルギー代謝の調節作用がある。難治癌の代謝を変える新しい治療法としてCPTは今後その有効性が十分期待できる考えられる。
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Report
(4 results)
Research Products
(11 results)
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[Journal Article] Cryptotanshinone suppresses tumorigenesis by inhibiting lipogenesis and promoting reactive oxygen species production in KRAS-activated pancreatic cancer cells2022
Author(s)
Tokio Terado, Chul Jang Kim, Akiyo Ushio, Kahori Minami, Yukihiro Tambe, Susumu Kageyama, Akihiro Kawauchi, Toshiyuki Tsunoda, Senji Shirasawa, Hiroyuki Tanaka, and Hirokazu Inoue
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Journal Title
International Journal of Oncology
Volume: in press
Related Report
Peer Reviewed
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[Journal Article] Antitumor activity of potent pyruvate dehydrogenase kinase 4 inhibitors from plants in pancreatic cancer.2019
Author(s)
Tambe, Y., Terado, T., Kim, C. J., Mukaisho, K., Yoshida, S., Sugihara, H., Tanaka, H., Chida, J., Kido, H., Yamaji, K., Yamamoto, T., Nakano, H., Omura, S. and Inoue, H.
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Journal Title
Molecular Carinogenesis 58, 1726-1737, 2019
Volume: 58
Issue: 10
Pages: 1726-1737
DOI
Related Report
Peer Reviewed
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