The alteration of the sphingolipid metabolism of anti-cancer drug resistant tumor cells and the overcome of these resistance by the phytochemicals

• Project/Area Number: 17K09025
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Laboratory medicine
• Research Institution: Chubu University
• Principal Investigator: MURATE Takashi 中部大学, 生命健康科学部, 教授 (30239537)
• Co-Investigator(Kenkyū-buntansha): 鈴木 元 藤田医科大学, 医学部, 教授 (80236017)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥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)
• 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

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.

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。

Research Products

• [Journal Article] Vaticanol C, a phytoalexin, induces apoptosis of leukemia and cancer cells by modulating expression of multiple sphingolipid metabolic enzymes (2020)
  • Author(s): Chisato Inoue, Sayaka Sobue, Naoki Mizutani, Yoshiyuki Kawamoto, Yuji Nishizawa, Masatoshi Ichihara, Toshiyuki Takeuchi, Fumihiko Hayakawa, Motoshi Suzuki, Tetsuro Ito, Yoshinori Nozawa, Takashi Murate
  • Journal Title: Nagoya Journal of Medical Sciences Volume: -
  • NAID: 120006847437
  • Peer Reviewed / Open Access
• [Journal Article] Involvement of MCL1, c-myc, and cyclin D2 protein degradation in ponatinib-induced cytotoxicity against T315I (+) Ph+leukemia cells (2020)
  • Author(s): Chisato Inoue, Sayaka Sobue, Yoshiyuki Kawamoto, Yuji Nishizawa, Masatoshi Ichihara, Akihiro Abe, Fumihiko Hayakawa, Motoshi Suzuki, Yoshinori Nozawa, Takahsi Murate
  • Journal Title: Biochem. Biophys. Res. Commun Volume: -
• [Journal Article] Inhibition of mast cell degranulation by melanin. (2019)
  • Author(s): Kawamoto Y, Kondo H, Hasegawa M, Kurimoto C, Ishii Y, Kato C, Botei T, Shinya M, Murate T, Ueno Y, Kawabe M, Goto Y, Yamamoto R, Iida M, Yajima I, Ohgami N, Kato M, Takeda K.
  • Journal Title: Biochem Pharmacol. Volume: 163 Pages: 178-193
  • DOI: 10.1016/j.bcp.2019.02.015
  • Peer Reviewed
• [Journal Article] Myonectin Is an Exercise-Induced Myokine That Protects the Heart From Ischemia-Reperfusion Injury. (2018)
  • Author(s): Otaka N, Shibata R, Ohashi K, Uemura Y, Kambara T, Enomoto T, Ogawa H, Ito M, Kawanishi H, Maruyama S, Joki Y, Fujikawa Y, Narita S, Unno K, Kawamoto Y, Murate T, Murohara T, Ouchi N.
  • Journal Title: Circ Res. Volume: 123 Issue: 12 Pages: 1326-1338
  • DOI: 10.1161/circresaha.118.313777
  • Peer Reviewed
• [Journal Article] BCL2 inhibitor ABT-199 and JNK inhibitor SP600125 exhibit synergistic cytotoxicity against imatinib-resistant Ph+ ALL cells. (2018)
  • Author(s): Inoue C, Sobue S, Aoyama Y, Mizutani N, Kawamoto Y, Nishizawa Y, Ichihara M, Abe A, Hayakawa F, Suzuki M, Nozawa Y, Murate T.
  • Journal Title: Biochem Biophys Rep. Volume: 15 Pages: 69-75
  • DOI: 10.1016/j.bbrep.2018.07.001
  • Peer Reviewed / Open Access
• [Journal Article] Modulation of the sphingolipid rheostat is involved in paclitaxel resistance of the human prostate cancer cell line PC3-PR (2016)
  • Author(s): Yuka Aoyama, Sayaka Sobue, Naoki Mizutani, Chisato Inoue, Yoshiyuki Kawamoto, Yuji Nishizawa, Masatoshi Ichihara, Mamoru Kyogashima, Motoshi Suzuki, Yoshinoti Nozawa, Takashi Murate
  • Journal Title: Biochem Biophys Res Commun Volume: 486 Issue: 2 Pages: 551-557
  • DOI: 10.1016/j.bbrc.2017.03.084
  • Peer Reviewed / Open Access
• [Presentation] BCL2 and JNK signaling pathway as the therapeutic target of imatinib-resistant Ph1-ALL cells, NphA2/STIR and MR87/STIR (2017)
  • Author(s): Inoue C, Sobue S, Aoyama Y, Mizutani N, Kawamoto Y, Ichihara M, Suzuki M, Nozawa Y, Abe A, Hayakawa F, Murate T, Nishizawa Y.
  • Organizer: 第４０回日本分子生物学会