Anti-tumor activity of potent PDK4 inhibitors from plants for KRAS-mutated intractable cancers

2021 Fiscal Year Final Research Report

• Project/Area Number: 19K07480
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 49030:Experimental pathology-related
• Research Institution: Shiga University of Medical Science
• Principal Investigator: Inoue Hirokazu 滋賀医科大学, 医学部, 非常勤講師 (30176440)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Keywords: Cryptotanshinone / PDK4 / K-Ras / 膵臓癌 / 脂質代謝 / 活性酸素

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.

Free Research Field

分子腫瘍学

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。