Targeting ceramide synthase 6-dependent metastasis-prone phenotype in lung cancer cells

• Project/Area Number: 26290051
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Partial Multi-year Fund
• Section: 一般
• Research Field: Tumor therapeutics
• Research Institution: Fujita Health University (2017-2018); Nagoya University (2014-2016)
• Principal Investigator: SUZUKI Motoshi 藤田医科大学, 医学部, 教授 (80236017)
• 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)
• Project Period (FY): 2014-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥16,510,000 (Direct Cost: ¥12,700,000、Indirect Cost: ¥3,810,000); Fiscal Year 2017: ¥3,380,000 (Direct Cost: ¥2,600,000、Indirect Cost: ¥780,000); Fiscal Year 2016: ¥3,380,000 (Direct Cost: ¥2,600,000、Indirect Cost: ¥780,000); Fiscal Year 2015: ¥6,630,000 (Direct Cost: ¥5,100,000、Indirect Cost: ¥1,530,000); Fiscal Year 2014: ¥3,120,000 (Direct Cost: ¥2,400,000、Indirect Cost: ¥720,000)
• Keywords: 肺癌 / 転移 / セラミド / 創薬 / 脂質 / アクチン / スフィンゴ脂質 / 肺がん / 分子標的薬 / 癌 / 代謝 / 薬剤 / 治療 / 抗がん剤 / 抗癌剤 / 低分子化合物

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.

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。

Research Products

• [Journal Article] ROR1-CAVIN3 interaction required for caveolae-dependent endocytosis and pro-survival signaling in lung adenocarcinoma (2019)
  • Author(s): Yamaguchi T, Hayashi M, Ida L, Yamamoto M, Lu C, Kajino T, Cheng J, Nakatochi M, Isomura H, Yamazaki M, Suzuki M, Fujimoto T, Takahashi T.
  • Journal Title: Oncogene Volume: - Issue: 26 Pages: 5142-5157
  • DOI: 10.1038/s41388-019-0785-7
  • Peer Reviewed / Open Access
• [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] Thyroid transcription factor-1-regulated miR-532-5p targets KRAS and MKL2 oncogenes and induces apoptosis in lung adenocarcinoma cells (2017)
  • Author(s): Griesing, S, Kajino T, Tai MC, Liu Z, Nakatochi M, Shimada Y, Suzuki M, Takahashi T
  • Journal Title: Cancer Sci Volume: 108 Issue: 7 Pages: 1394-1404
  • DOI: 10.1111/cas.13271
  • 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
• [Journal Article] Mechanism of paclitaxel resistance in a human prostate cancer cell line, PC3-PR, and its sensitization by cabazitaxel (2016)
  • Author(s): Sobue S, Mizutani N, Aoyama Y, Kawamoto Y, Suzuki M, Nozawa Y, Ichihara M, Murate T
  • Journal Title: Biochem Biophys Res Commun Volume: 479 Issue: 4 Pages: 808-813
  • DOI: 10.1016/j.bbrc.2016.09.128
  • Peer Reviewed
• [Journal Article] Effect of pH on the Misincorporation Rate of DNA Polymerase η (2016)
  • Author(s): Nishimoto N, Suzuki M, Izuta S
  • Journal Title: Biological and Pharmaceutical Bulletin Volume: 39 Issue: 6 Pages: 953-958
  • DOI: 10.1248/bpb.b15-00900
  • NAID: 130005155145
  • ISSN: 0918-6158, 1347-5215
  • Peer Reviewed
• [Journal Article] CERS6発現と転移能 (2016)
  • Author(s): 鈴木元、高橋隆
  • Journal Title: がん分子標的治療 Volume: 14 Pages: 103-107
• [Journal Article] Targeting ceramide synthase 6-dependent metastasis-prone phenotype in lung cancer cells. (2016)
  • Author(s): Suzuki M, et al.
  • Journal Title: J. Clin. Invest. Volume: 126 Issue: 1 Pages: 254-265
  • DOI: 10.1172/jci79775
  • Peer Reviewed / Open Access
• [Journal Article] Receptor tyrosine kinase-like orphan receptor 1, a target of NKX2-1/TTF-1 lineage-survival oncogene, inhibits apoptosis signal-regulating kinase 1-mediated pro-apoptotic signaling in lung adenocarcinoma (2016)
  • Author(s): Ida L, Yamaguchi T, Yanagisawa K, Kajino T, Shimada Y, Suzuki M, Takahashi T
  • Journal Title: Cancer Sci Volume: 107 Issue: 2 Pages: 155-161
  • DOI: 10.1111/cas.12858
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] ROR1 sustains caveolae and survival signaling as a scaffold of cavin-1 and caveolin-1 (2016)
  • Author(s): Yamaguchi T, Lu C, Yanagisawa K, Can Lu, Usukura J, Cheng J, Hotta N, Shimada Y, Ida R, Isomura H, Suzuki M, Fujimoto T, Takahashi T
  • Journal Title: Nat Commun Volume: 7 Issue: 1 Pages: 10060-10060
  • DOI: 10.1038/ncomms10060
  • Peer Reviewed / Open Access
• [Journal Article] Resveratrol-induced transcriptional up-regulation of ASMase (SMPD1) of human leukemia and cancer cells. (2016)
  • Author(s): Mizutani N, Omori Y, Kawamoto Y, Sobue S, Ichihara M, Suzuki M, Kyogashima M, Nakamura M, Tamiya-Koizumi K, Nozawa Y, Murate T.
  • Journal Title: Biochem Biophys Res Commun Volume: 470 Issue: 4 Pages: 851-856
  • DOI: 10.1016/j.bbrc.2016.01.134
  • Peer Reviewed
• [Journal Article] Effect of pH on the misincorporation rate of DNA polymerase eta (2016)
  • Author(s): Nishimoto N, Suzuki, M, Izuta S
  • Journal Title: Biol Pharm Bull Volume: in press
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Increased Acid Ceramidase Expression depends on Upregulation of Androgen-dependent Deubiquitinases, USP2, in a Human Prostate Cancer Cell Line, LNCaP. (2015)
  • Author(s): Naoki Mizutani, Minami Inoue, Yukari Omori, Hiromi Ito, Keiko Tamiya-Koizumi, Akira Takagi, Tetsuhito Kojima, Mitsuhiro Nakamura, Soichiro Iwaki, Masahiro Nakatochi, Motoshi Suzuki, Yoshinori Nozawa, Takashi Murate
  • Journal Title: J. Biochem. Volume: 印刷中 Issue: 4 Pages: 309-319
  • DOI: 10.1093/jb/mvv039
  • Peer Reviewed
• [Journal Article] miR-342-3p regulates MYC transcriptional activity via direct repression of E2F1 in human lung cancer. (2015)
  • Author(s): Tai MC, Kajino T, Nakatochi M, Arima C, Shimada Y, Suzuki M, Miyoshi H, Yatabe Y, Yanagisawa K, Takahashi T.
  • Journal Title: Carcinogenesis Volume: 36 Pages: 1464-1473
  • DOI: 10.1093/carcin/bgv152
  • Peer Reviewed
• [Journal Article] Increased SPHK2 transcription of human colon cancer cells in serum-depleted culture: the involvement of CREB transcription factor. (2015)
  • Author(s): Mizutani N, Omori Y, Tanaka K, Ito H, Takagi A, Kojima T, Nakatochi M, Ogiso H, Kawamoto Y, Nakamura M, Suzuki M, Kyogashima M, Koizumi K, Nozawa Y, Murate T.
  • Journal Title: J Cell Biochem Volume: 116 Issue: 10 Pages: 2227-2238
  • DOI: 10.1002/jcb.25173
  • Peer Reviewed
• [Journal Article] Increased Acid Ceramidase Expression depends on Upregulation of Androgen-dependent Deubiquitinases, USP2, in a Human Prostate Cancer Cell Line, LNCaP (2015)
  • Author(s): Mizutani N, Inoue M, Omori Y, Ito H, Tamiya-Koizumi K, Takagi A, Kojima T, Nakamura M, Iwaki S, Nakatochi M, Suzuki M, Nozawa Y, and Murate M
  • Journal Title: J Biochem Volume: in press
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Phosphorylated Sp1 is the regulator of DNA-PKcs and DNA ligase IV transcription of daunorubicin-resistant leukemia cell lines. (2014)
  • Author(s): Nishida Y, Mizutani N, Inoue M, Omori Y, Tamiya-Koizumi K, Takagi A, Kojima T, Suzuki M, Nozawa Y, Minami Y, Ohnishi K, Naoe T, Murate T.
  • Journal Title: Biochim Biophys Acta. Volume: 1839 Issue: 4 Pages: 265-274
  • DOI: 10.1016/j.bbagrm.2014.02.004
  • Peer Reviewed
• [Journal Article] Downregulation of POLD4 in Calu6 cells results in G1-S blockage through suppression of the Akt-Skp2-p27 pathway (2014)
  • Author(s): Huang Q, Suzuki M, Zeng Y, Zhang H, Yang D, Lin H
  • Journal Title: Bioorg Med Chem Lett Volume: 24 Issue: 7 Pages: 1780-1783
  • DOI: 10.1016/j.bmcl.2014.02.033
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Lung adenocarcinoma subtypes definable by lung development-related miRNA expression profiles in association with clinicopathologic features (2014)
  • Author(s): Arima C, Kajino T, Tamada Y, Imoto S, ShimadaY, Nakatochi, M, Suzuki M, Isomura H, Yatabe Y, Yamaguchi T, Yanagisawa K, Miyano S, Takahashi T
  • Journal Title: Carcinogenesis Volume: 35 Issue: 10 Pages: 2224-2231
  • DOI: 10.1093/carcin/bgu127
  • Peer Reviewed / Acknowledgement Compliant
• [Presentation] DNA polymerase delta and cancer. (2018)
  • Author(s): Suzuki M
  • Organizer: Fidelity, Mutations in Cancer Symposium
  • Int'l Joint Research / Invited
• [Presentation] A metastasis protein CERS6 is transcriptionally regulated by miR-101 and YB-1. (2018)
  • Author(s): Hanxiao Shi, Toshiyuki Takeuchi, Atsuko Niimi, Yasuyoshi Mizutani, Takashi Murate, Takashi Suzuki, Motoshi Suzuki
  • Organizer: 第76回日本癌学会総会
• [Presentation] CERS6-dependent Sphingolipid Profile Regulates Lung Cancer Pathogenesis and Metastasis (2017)
  • Author(s): Suzuki M
  • Organizer: The 4th International Symposium of Gunma University Initiative for Advanced Research (GIAR)
  • Int'l Joint Research / Invited
• [Presentation] Targeting ceramide synthase 6-dependent metastasis-prone phenotype in lung cancer cells (2017)
  • Author(s): Suzuki M
  • Organizer: 第55回日本生物物理学会年会
  • Int'l Joint Research / Invited
• [Presentation] 41.CERS6-dependent Sphingolipid Profile Regulates Lung Cancer Pathogenesis and Metastasis (2017)
  • Author(s): Motoshi Suzuki, Takashi Murate, Mamoru Kyogashima, Yuji, Komizu, Yoko Matsumoto, Takashi Takahashi
  • Organizer: 第76回日本癌学会総会
• [Presentation] 肺がん転移におけるセラミドの役割とそれを利用した治療法の開発 (2017)
  • Author(s): 鈴木元
  • Organizer: 第12回スフィンゴテラピィ研究会
• [Presentation] Targeting CERS6-dependent Sphingolipid Homeostasis in Lung Cancer Cells (2016)
  • Author(s): Suzuki M, Murate T, Kyogashima M and Takahashi T
  • Organizer: 第75回日本癌学会学術総会
  • Place of Presentation: パシフィコ横浜（神奈川県横浜市）
  • Year and Date: 2016-10-06
• [Presentation] 39.TTF-1/NKX2-1-inducedmiR-532-5ptargetsKRASandMKL2 oncogenes and causes apoptosis in lung adenocarcinoma cells (2016)
  • Author(s): Sebastian Griesing, Taisuke Kajino, Mei Chee Tai, Zhuoran Liu, Masahiro Nakatochi, Motoshi Suzuki, Takashi Takahashi
  • Organizer: 第75回日本癌学会総会
  • Place of Presentation: パシフィコ横浜（神奈川県横浜市）
  • Year and Date: 2016-10-06
• [Presentation] 40.TTF-1/NKX2-1bindstoDDB1andconfersreplicationstress resistance to lung adenocarcinomas (2016)
  • Author(s): Zhuoran Liu, Kiyoshi Yanagisawa, Sebastian Griesing, Mika Iwai, Taisuke Kajino, Motoshi Suzuki, Takashi Takahashi
  • Organizer: 第75回日本癌学会総会
  • Place of Presentation: パシフィコ横浜（神奈川県横浜市）
  • Year and Date: 2016-10-06
• [Presentation] Targeting CERS6-dependent Sphingolipid Pathway in Lung Cancer Cells (2015)
  • Author(s): Motoshi Suzuki, Takashi Murate, Mamoru Kyogashima and Takashi Takahashi
  • Organizer: 第74回日本癌学会総会
  • Place of Presentation: 愛知県名古屋国際会議場
  • Year and Date: 2015-10-08
• [Presentation] セラミド合成酵素CerS6 の肺癌における役割とそれを利用した治療法の開発 (2015)
  • Author(s): 鈴木元
  • Organizer: 国際高等研究所研究プロジェクト「分子基盤に基づく生体機能への揺らぎとダイナミックネットワークの解明」
  • Place of Presentation: 京都府木津川市国際高等研究所
  • Year and Date: 2015-03-17
  • Invited
• [Presentation] A pivotal role of CERS6 on the sphingolipid metabolic pathways and tumor metastasis in lung cancer (2014)
  • Author(s): Suzuki M, Murate T, Kyogashima M and Takahashi T
  • Organizer: 第73回日本癌学会学術総会
  • Place of Presentation: 神奈川県横浜市パシフィコ横浜
  • Year and Date: 2014-09-27
• [Presentation] 悪性腫瘍におけるスフィンゴ脂質代謝の果たす役割 (2014)
  • Author(s): 鈴木元
  • Organizer: 第15回Pharmaco-Hematologyシンポジウム
  • Place of Presentation: 愛知県名古屋市名古屋市立大学
  • Year and Date: 2014-05-23
  • Invited
• [Book] がん生物学イラストレーテッド（がんとmicroRNAセクション） (2019)
  • Author(s): 水谷泰嘉、鈴木元
  • Publisher: 羊土社
• [Patent(Industrial Property Rights)] がん転移抑制剤 (2019)
  • Inventor(s): 鈴木元、竹内俊幸、高橋隆、磯村久徳、小泉惠子、安藤隆幸
  • Industrial Property Rights Holder: 鈴木元、竹内俊幸、高橋隆、磯村久徳、小泉惠子、安藤隆幸
  • Industrial Property Rights Type: 特許
  • Filing Date: 2019