Investigation for the proliferation mechanism of lung cancer stem cells

• Project/Area Number: 23890020
• Research Category: Grant-in-Aid for Research Activity Start-up
• Allocation Type: Single-year Grants
• Research Field: Thoracic surgery
• Research Institution: Tohoku University
• Principal Investigator: SUZUKI Takaya 東北大学, 加齢医学研究所, 非常勤講師 (80611996)
• Project Period (FY): 2011 – 2012
• Project Status: Completed (Fiscal Year 2012)
• Budget Amount: ¥3,250,000 (Direct Cost: ¥2,500,000、Indirect Cost: ¥750,000); Fiscal Year 2012: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2011: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: 癌幹細胞 / 海洋由来天然化合物 / マクロリド化合物 / 肺癌 / 肺癌幹細胞 / 海洋由来マクロリド化合物 / Erk / Akt / PKC / MAPキナーゼカスケード / Aktシグナル

Research Abstract

Previously we identified the lung specific tissue stem cells named alveolar epithelial progenitor cells (AEPCs). The novel marine macrolide (-)-exiguolide significantly inhibit the proliferation of AEPCs. We hypothesized that (-)-exiguolide inhibit proliferation of lung cancer stem cells. Global gene expression analysis suggested the involvement of protein kinase C (PKC), extracellular regulated kinase and phosphoinositide 3 kinase (PI3K)/Akt signalling pathway in the tumour inhibition of (-)-exiguolide. Western blotting analysis confirmed the potential activity of (-)-exiguolide; p21 up-regulation through PKCα activation, MEK inhibition and PI3K/Akt/GSK3β pathway modulation resulting in apoptosis.

Research Products

• [Journal Article] Increased severity of H1N1 pandemic influenza virus infection in alveolar typeII cells from patients with pulmonary fibrosis (2013)
  • Author(s): Fujino N, Kubo H, Ota C, Suzuki T, Takahashi T, Yamada M, Suzuki S, Kondo T, Nagatomi R, Tando Y, Yamaya M.
  • Journal Title: J Infect Dis Volume: 207 Pages: 692-693
  • Peer Reviewed
• [Journal Article] Total synthesis and biological evaluation of (-)-exiguolide analogues: Importance of the macrocyclic backbone (2013)
  • Author(s): Haruhiko Fuwa, Kana Mizunuma, Makoto Sasaki, Takaya Suzuki, Hiroshi Kubo
  • Journal Title: Organic & Bimolecular Chemistry Volume: 11 Issue: 21 Pages: 3442-3450
  • DOI: 10.1039/c3ob40131f
  • Peer Reviewed
• [Journal Article] Administration of a specific inhibitor of neutrophil elastase attenuates pulmonary fibrosis after acute lung injury in mice (2012)
  • Author(s): Fujino N, Kubo H, Suzuki T, He M, Suzuki T, Yamada M, Takahashi T, Ota C, Yamaya M.
  • Journal Title: Exp Lung Res Volume: 38 Pages: 28-36
  • Peer Reviewed
• [Journal Article] Analysis of gene expression profiles in alveolar epithelial type II-like cells differentiated from human alveolar epithelial progenitor cells (2012)
  • Author(s): Fujino N, Ota C, Suzuki T, Suzuki S, Hegab AE, Yamada M, Takahashi T, HeM, Kondo T, Kato H, Yamaya M, Kubo H.
  • Journal Title: Respir Invest Volume: 50 Pages: 110-116
  • Peer Reviewed
• [Journal Article] Surgical stress increases circulating endothelial microparticles inthe elderly (2012)
  • Author(s): Takahashi T, Kubo H, Fujino N, Suzuki T, Ota C, Yamada M, Yamaya M, Suzuki S, Kurosawa S.
  • Journal Title: Anaesthesia & Intensive Care Volume: 40 Pages: 899-902
  • Peer Reviewed
• [Journal Article] A novel method for isolating individual cellular components from the adult human distal lung (2012)
  • Author(s): Fujino N, Kubo H, Ota C, Suzuki T, Suzuki S, Yamada M, Takahashi T, He M, Suzuki T, Kondo T, Yamaya M.
  • Journal Title: Am J Respir Cell Mol Biol Volume: 46 Pages: 422-430
  • Peer Reviewed
• [Journal Article] Gene expression profiles of alveolar type II cells of chronic obstructive pulmonary disease: A case-control study (2012)
  • Author(s): Fujino N, Ota C, Takahashi T, Suzuki T, Suzuki S, Yamada M, Nagatomi R, Kondo T, Yamaya M, Kubo H
  • Journal Title: BMJ Open Volume: 2 Issue: 6 Pages: e001553-e001553
  • DOI: 10.1136/bmjopen-2012-001553
  • Peer Reviewed
• [Journal Article] Increased circulating endothelial microparticles in COPD patients: a potential biomarker for COPD exacerbation susceptibility (2012)
  • Author(s): Takahashi T, Kobayashi S, Fujino N, Suzuki T, Ota C, He M, Yamada M, Suzuki S, Yanai M, Kurosawa S, Yamaya M, Kubo H.
  • Journal Title: Thorax Volume: 67 Pages: 1067-1074
  • Peer Reviewed
• [Journal Article] Total synthesis and biological assessment of (-)-exiguolide and analogues (2011)
  • Author(s): Fuwa H, Suzuki T, Kubo H, Yamori T, Sasaki M.
  • Journal Title: Chemistry-A European Journal Volume: 17 Pages: 2678-2688
  • Peer Reviewed
• [Journal Article] Theincrease in surface CXCR4 expression on lung extravascular neutrophils and its effects on neutrophils during endotoxin-induced lung injury (2011)
  • Author(s): Yamada M, Kubo H, Kobayashi S, Ishizawa K, He M, Suzuki T, Fujino N, Kunishima H, Hatta M, Nishimaki K, Aoyagi T, Tokuda K, Kitagawa M, Yano H, Tamamura H, Fujii N, Kaku M.
  • Journal Title: Cellular& Molecular Immunology Volume: 5 Pages: 305-314
  • Peer Reviewed
• [Journal Article] Isolation of alveolar epithelial type II progenitor cells from adult humanlungs (2011)
  • Author(s): Fujino N, Kubo H, Suzuki T, Ota C, Hegab AE, He M, Suzuki S, Suzuki T, Yamada M, Kondo T, Kato H, Yamaya M.
  • Journal Title: Lab Invest Volume: 91 Pages: 363-378
  • Peer Reviewed
• [Journal Article] RAGE binds phosphatidylserine and assists in the clearance of apoptotic cells (2011)
  • Author(s): He M, Kubo H, Morimoto K, Fujino N, Suzuki T, Takahashi T, Yamada M, Yamaya M, Maekawa T, Yamamoto Y, Yamamoto H.
  • Journal Title: EMBO Reports Volume: 12 Pages: 358-364
  • Peer Reviewed
• [Journal Article] Evidence for Human Lung Stem Cells (correspondence) (2011)
  • Author(s): Suzuki T, Kondo T, Kubo H.
  • Journal Title: New Engl J Med Volume: 365 Pages: 464-466
  • Peer Reviewed
• [Journal Article] Evidence for human lung stem cell (Correspondence) (2011)
  • Author(s): 鈴木隆哉, 久保裕司, 近藤丘
  • Journal Title: New England Journal of Medicine Volume: 365 Pages: 464-466
  • Peer Reviewed
• [Journal Article] Total synthesis and biological assessment of (-)-exiguolide and analogues (2011)
  • Author(s): 不破晴彦, 鈴木隆哉, 久保裕司, 他
  • Journal Title: Chemistry-A Europian Journal Volume: 17 Pages: 2678-2688
  • Peer Reviewed
• [Journal Article] Isolation of alveolar epithelial type II progenitor cells from adult human lungs (2011)
  • Author(s): 藤野直也, 久保裕司, 鈴木隆哉, 他
  • Journal Title: Laboratory Investigation Volume: 91 Pages: 363-378
  • Peer Reviewed
• [Presentation] An anti-cancer effect of newly synthesized marine macrolide,(-)-Exiguolide (2012)
  • Author(s): Suzuki T, Kubo H, Yamada M, Fuwa H, Fujino N, Takahashi T, Ota C, Yamaya M, Kondo T.
  • Organizer: Am J Respir Crit Care Med 2012;185:A6278
  • Place of Presentation: サンフランシスコ,米国
  • Year and Date: 2012-05-23
• [Presentation] 海洋生物由来新規マクロリド化合物Exiguolideの抗腫瘍作用 (2011)
  • Author(s): 鈴木隆哉, 近藤丘
  • Organizer: 日本肺癌学会
  • Place of Presentation: 大阪
  • Year and Date: 2011-11-04
• [Presentation] An anti-cancer effect of newly synthesized marine compounds. American Thoracic Society International Conference 2011 (2011)
  • Author(s): Suzuki T, Kubo H, Fuwa H, Kondo T.
  • Organizer: Am J Respir Crit CareMed 2011;183:A5069
  • Place of Presentation: デンバー,米国
  • Year and Date: 2011-05-17
• [Presentation] An anti-cancer effect of newly synthesized marine macrolide, (-)-Exiguolide
  • Author(s): Suzuki, T
  • Organizer: American Thoracic Society International Conference 2012
  • Place of Presentation: サンフランシスコ・アメリカ合衆国
• [Presentation] 海洋由来新規マクロリド化合物Exiguolideの抗腫瘍作用
  • Author(s): 鈴木隆哉
  • Organizer: 第65回日本胸部外科学会定期学術集会
  • Place of Presentation: 福岡
• [Patent(Industrial Property Rights)] 抗がん作用を有するマクロライド化合物 (2011)
  • Inventor(s): 不破春彦,佐々木誠,久保裕司,鈴木隆哉
  • Industrial Property Rights Holder: 国立大学法人東北大学
  • Filing Date: 2011-10-23
  • Overseas
• [Patent(Industrial Property Rights)] 抗がん作用を有するマクロライド化合物 (2011)
  • Inventor(s): 不破春彦, 佐々木誠, 久保裕司, 鈴木隆哉
  • Industrial Property Rights Holder: 東北大学
  • Filing Date: 2011-10-23
  • Overseas