| Project/Area Number |
17K09025
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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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| Research Field |
Laboratory medicine
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| Research Institution | Chubu University |
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Principal Investigator |
MURATE Takashi 中部大学, 生命健康科学部, 教授 (30239537)
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| Co-Investigator(Kenkyū-buntansha) |
鈴木 元 藤田医科大学, 医学部, 教授 (80236017)
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| Project Period (FY) |
2017-04-01 – 2020-03-31
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| Project Status |
Completed (Fiscal Year 2019)
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| Budget Amount *help |
¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000)
Fiscal Year 2019: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2017: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
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| Keywords | tumor cell / anti cancer drug / resistance / paclitaxel / resveratrol / vaticanol C / sphingolipid / apoptosis / sphingolipid metabolism / anti-cancer drug / sphingosine kinase / GCS / Ph+ALL / imatinib resistance / BCL2 inhibitor / JNK inhibitor / synergistic action / paclitaxel resistance / prostate cancer cell / SPHK1 / ASMase and NSMase2 / proteazome inhibitor / HDAC inhibitor / スフィンゴ脂質 / 腫瘍細胞 / 抗がん剤耐性 / ファイトケミカル / 耐性の克服 |
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| Outline of Final Research Achievements |
We have published 2 papers concerning this research project. The fist one is the analysis of paclitaxel (PTX)-resistance prostate cancer cell line (PC3-PR) and its parental cell line (PC3) (BBRC 2017). PTX increased cellular ceramides of PC3 but not PC3-PR and that PC3-PR exhibited increased expression of sphingosine kinase 1 and glucosylceramide synthase as well as decrease of acid and neutral sphingomyelinases. The alteration of these enzymes could modulate PTX sensitivity. The second one is the analysis of resveratrol (RVT) oligomer, vaticanol C (VTC). Based on the previous paper describing the superior cytotoxicity of VCT to RVT (Carcinogenesis 2003), we analyzed RVT and its oligomers, and confirmed the robust cytotoxicity of VTC. Further analysis showed that anti-caner drug resistant cancer cells with different mechanisms were all sensitive to VTC due to the apoptotic mechanism. We also found that VTC increased cellular ceramides and decreased cellular S1P.
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| Academic Significance and Societal Importance of the Research Achievements |
今回の研究により、抗がん剤耐性腫瘍細胞におけるスフィンゴ脂質代謝の変化がその抗がん剤耐性の一因となっている事が明らかになり、sphingosine kinase 1あるいはglucosylceramide synthaseの阻害剤あるいはsiRNAが抗がん剤耐性をある程度克服出来る事を示した。更にファイトケミカルであるレスベラトロール４量体のバチカノールCが、レスベラトロールよりも低濃度で強力な殺細胞効果を示す事、さらにはその効果発現にもバチカノールCがスフィンゴ脂質代謝酵素の発現レベルを修飾する事が一因である事を証明した。我々の研究が、将来の臨床応用にむけて追求すべき研究分野を提示した。
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