Identification of cancer initiating cell factors and an attempt of drug development

• Project/Area Number: 26670625
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Respiratory surgery
• Research Institution: Nagoya University
• Principal Investigator: SUZUKI Motoshi 名古屋大学, 医学(系)研究科(研究院), 講師 (80236017)
• Co-Investigator(Kenkyū-buntansha): FUKUI Takayuki 名古屋大学, 医学部附属病院, 病院講師 (70463198) ; WAKAHARA Keiko 名古屋大学, 医学部附属病院, 病院講師 (00631433) ; KATO Sei-ichi 名古屋大学, 大学院医学系研究科, 講師 (30584669) ; Nishida Atsushi 千葉大学, 大学院薬学研究院, 教授 (80130029)
• Project Period (FY): 2014-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥3,640,000 (Direct Cost: ¥2,800,000、Indirect Cost: ¥840,000); Fiscal Year 2015: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2014: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: 肺がん / がん幹細胞 / 低分子化合物 / 肺癌 / 抗癌剤 / 分子標的治療薬

Outline of Final Research Achievements

We collected clinical lung cancer specimens and transplanted each of in the immune-deficient mice. Xenografts were recovered after tumor formation, collagenase-treated, and sorted for CD166 positive population. In a cell line, the CD166 positive cells successfully formed secondary tumors in mice. We performed database analysis to figure out a gene candidate which may contribute to the cancer initiating cell nature. By using the above cell line, we established a stable cell line that is associated with a knockdown of this gene, and inoculated thousands of cells in mice. Results are forthcoming. We also screened for an inhibitor against this gene product. Among the 2000 candidates, we found a compound that inhibits the activity. To decrease the EC50 value, we started optimization of this compound.

Research Products

• [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] 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: Biochemical and Biophysical Research Communication Volume: 470 Pages: 851-856
  • DOI: 10.1016/j.bbrc.2016.01.134
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] ROR1 sustains caveolae and survival signalling 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: Nature Communication Volume: 7 Pages: 10060-10060
  • DOI: 10.1038/ncomms10060
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Targeting CERS6-dependent metastasis-prone phenotype in lung cancer cells (2016)
  • Author(s): Suzuki M, et al.
  • Journal Title: J Clin Invest. Volume: 126 Pages: 254-265
  • DOI: 10.1172/jci79775
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] ROR1, a target of NKX2-1/TTF-1 lineage-survival oncogene, inhibits ASK1-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 Science Volume: 107 Pages: 155-161
  • DOI: 10.1111/cas.12858
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Increased acid ceramidase expression depends on up regulation of androgen-dependent deubiquitinase, USO2, in a human proatate cancer cell line, LNCaP (2016)
  • 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, Murate T
  • Journal Title: J Biochem. Volume: 158 Pages: 309-319
  • DOI: 10.1093/jb/mvv039
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] miR-342-3p regulates MYC transcriptional activity via direct repression of E2F1 in human lung cancer. (2016)
  • 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 / Acknowledgement Compliant
• [Journal Article] SVA retrotransposition in exon 6 of the coagulation factor IX gene causing severe hemophilia B. (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 Pages: 134-139
  • DOI: 10.1002/jcb.25173
  • 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): 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 Pages: 265-274
  • DOI: 10.1016/j.bbagrm.2014.02.004
  • Peer Reviewed / Acknowledgement Compliant
• [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 Pages: 1780-1783
  • DOI: 10.1016/j.bmcl.2014.02.033
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Lung adenocarcinoma diversity 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 Pages: 2224-2231
  • DOI: 10.1093/carcin/bgu127
  • Peer Reviewed / Acknowledgement Compliant
• [Presentation] 1.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: 愛知県名古屋市名古屋国際会議場
  • 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