2018 Fiscal Year Final Research Report
Targeting ceramide synthase 6-dependent metastasis-prone phenotype in lung cancer cells
| Project/Area Number |
26290051
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Partial Multi-year Fund |
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| Section | 一般 |
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| Research Field |
Tumor therapeutics
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| Research Institution | Fujita Health University (2017-2018)
Nagoya University (2014-2016) |
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Principal Investigator |
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| Co-Investigator(Kenkyū-buntansha) |
村手 隆 中部大学, 生命健康科学部, 教授 (30239537)
西田 篤司 千葉大学, 大学院薬学研究院, 教授 (80130029)
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| Project Period (FY) |
2014-04-01 – 2019-03-31
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| Keywords | 肺癌 / 転移 / セラミド / 創薬 / 脂質 |
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| Outline of Final Research Achievements |
We analyzed NSCLC specimens and cell lines and determined that ceramide synthase 6 (CERS6) is markedly overexpressed compared with controls. Elevated CERS6 expression was due in part to reduction of microRNA-101 (miR-101) and was associated with increased invasion and poor prognosis. CERS6 knockdown in NSCLC cells altered the ceramide profile, resulting in decreased cell migration and invasion in vitro, and decreased the frequency of RAC1-positive lamellipodia formation while CERS6 overexpression promoted it. Furthermore, combined treatment with l-α-dimyristoylphosphatidylcholine liposome and the glucosylceramide synthase inhibitor D-PDMP induced cell death in association with ceramide accumulation and promoted cancer cell apoptosis and tumor regression in murine models. These results suggest that targeting this homeostasis has potential as a therapeutic strategy for CERS6-overexpressing NSCLC.
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| Free Research Field |
腫瘍学
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| Academic Significance and Societal Importance of the Research Achievements |
肺癌は年間死亡者数が癌腫の中で一位であり、新規肺癌患者は世界で年間130万人に上る。発癌機序の解明と発癌機序に基づく治療法の開発を目指す本研究は大いに意義がある。さらに、CERS6下流経路阻害を利用した抗腫瘍薬について：従来の分子標的治療薬は主にキナーゼを標的とした阻害剤（抗体）である。本研究は、単に分子標的活性を阻害するという発想ではなく、CERS6を高発現して、アポトーシス中間体であるセラミドを産生しているという癌細胞の代謝特性を利用するという発想に基づく。このアプローチに学術的な特色・独創性がある。
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