Intracellular transport and function of cancer- and neurodegenerative disease-related glycosphingolipids

• Project/Area Number: 22790280
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Single-year Grants
• Research Field: General medical chemistry
• Research Institution: Nagoya University
• Principal Investigator: YAMAUCHI Yoshio 名古屋大学, 医学(系)研究科(研究院), 講師 (00444878)
• Project Period (FY): 2010-10-20 – 2014-03-31
• Project Status: Completed (Fiscal Year 2013)
• Budget Amount: ¥2,860,000 (Direct Cost: ¥2,200,000、Indirect Cost: ¥660,000); Fiscal Year 2012: ¥650,000 (Direct Cost: ¥500,000、Indirect Cost: ¥150,000); Fiscal Year 2011: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2010: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
• Keywords: スフィンゴ糖脂質 / ガングリオシド / がん / 神経変成疾患 / 癌 / 神経変性疾患 / 細胞内輸送 / 脂質ラフト / ニーマン-ピック病 / メラノーマ / 糖脂質 / ニーマン・ピックC型病

Research Abstract

Glycosphingolipids (GSLs) are involved in pathophysiology of cancer and neurodegenerative disorders. In this work, I studied cellular distribution and functionalities of gangliosides associated to malanoma, a skin cancer and to Niemann-Pick type C (NPC) disease, a neurodegenerative disorder. The results showed that the melanoma-associated antigen ganglioside GD3 plays a role in the activation of the regulatory factor involved in lipid biosynthesis, which promotes lipid biosynthesis for the integrity of membrane microdomains in human melanoma cells. Pharmacological inhibition of the regulatory factor prevented tumor growth. Also, I studied cellular distribution of gangliosides related to NPC disease in NPC cells. The results showed that disease-associated gangliosides accumulate in the lysosome. Several small-molecules that promote their redistribution from the lysosome to cell surface were identified.

Research Products

• [Journal Article] Fine tuning of cell signals by glycosylation (2012)
  • Author(s): Furukawa K, Ohkawa Y, Yamauchi Y, Hamamura K, Ohmi Y, Furukawa K.
  • Journal Title: J Biochem. Volume: 151 Issue: 6 Pages: 573-578
  • DOI: 10.1093/jb/mvs043
  • NAID: 10031166098
  • Peer Reviewed
• [Journal Article] Essential roles of gangliosides in the formation and maintenance of membrane microdomains in brain tissues. (2012)
  • Author(s): Yuhsuke Ohmi
  • Journal Title: Neurochemical Research Volume: 37 Issue: 6 Pages: 1185-1191
  • DOI: 10.1007/s11064-012-0764-7
  • Peer Reviewed
• [Journal Article] Wisp2/CCN5 up-regulated in the central nervous system of GM3-only mice facilitates neurite formation in Neuro2a cells via integrin-Akt signaling (2011)
  • Author(s): Ohkawa, Y., Ohmi, Y, Tajima, O., Yamauchi, Y, Furukawa, K., Furukawa' K
  • Journal Title: Biochem.Biophys.Res.Commun. Volume: 411 Issue: 3 Pages: 483-489
  • DOI: 10.1016/j.bbrc.2011.06.118
  • Peer Reviewed
• [Journal Article] Functional activation of Src family kinase Yes is essential for the enhanced malignant properties of human melanoma cells expressing ganglioside GD3 (2011)
  • Author(s): Hamamura, K., Tsuji, M., Hotta, H., Ohkawa, Y., Takahashi, M., Shibuya, H., Nakashima, H., Yamauchi, Y., Hashimoto, N., Hattori, H., Ueda, M., Furukawa, K., Furukawa. K
  • Journal Title: J.Biol.Chem. Volume: 286 Issue: 21 Pages: 18526-37
  • DOI: 10.1074/jbc.m110.164798
  • Peer Reviewed
• [Journal Article] Positive feedback loop between PI3K-Akt-mTORC1 signaling and the lipogenic pathway boosts Akt signaling : induction of the lipgenic pathway by a melanoma antigen (2011)
  • Author(s): Yamauchi Y, Furukawa K, Hamamura K, Furukawa K.
  • Journal Title: Cancer Res. Volume: 71 Issue: 14 Pages: 4989-4997
  • DOI: 10.1158/0008-5472.can-10-4108
  • Peer Reviewed
• [Journal Article] Gangliosides are essential in the protection of inflammation and neuro degeneration via maintenance of lipid rafts: elucidation by a series of ganglioside-deficient mutant mice (2011)
  • Author(s): Ohmi, Y., Tajima, O., Ohkawa, Y., Sugiura, Y., Furukawa, K., Furukawa, K.
  • Journal Title: J.Neurochem. Volume: 116 Issue: 5 Pages: 926-935
  • DOI: 10.1111/j.1471-4159.2010.07067.x
  • Peer Reviewed
• [Journal Article] Functional activation of Src family kinase yes protein is essential for the enhanced malignant properties of human melanoma cells expressing ganglioside GD3 (2011)
  • Author(s): Hamamura K, Tsuji M, Hotta H, Ohkawa Y, Takahashi M, Shibuya H, Nakashima H, Yamauchi Y, Hashimoto N, Hattori H, Ueda M, Furukawa K, Furukawa K
  • Journal Title: J.Biol.Chem. Volume: 286 Pages: 18526-18537
  • Peer Reviewed
• [Journal Article] Gangliosides are essential in the protection of inflammation and neuro degeneration via maintenance of lipid rafts : elucidation by a series of ganglioside-deficient mutant mice. (2011)
  • Author(s): Ohmi Y, Tajima O, Ohkawa Y, Yamauchi Y, Sugiura Y, Furukawa K, Furukawa K.
  • Journal Title: J Neurochem Volume: 116 Pages: 926-935
  • Peer Reviewed
• [Journal Article] GM1/GD1b/GA1 synthase expression results in the reduced cancer phenotypes with modulation of composition and raft-localization of gangliosides in a melanoma cell line (2010)
  • Author(s): Dong Y, Ikeda K, Hamamura K,Zhang Q, Kondo Y, Matsumoto Y, Ohmi Y, Yamauchi Y, Furukawa K, Taguchi R, Furukawa K.
  • Journal Title: Cancer Sci. Volume: 101 Issue: 9 Pages: 2039-2047
  • DOI: 10.1111/j.1349-7006.2010.01613.x
  • NAID: 10027831670
  • Peer Reviewed
• [Journal Article] Ganglioside GD3 enhances adhesion signals and augments malignant properties of melanoma cells by recruiting integrins to glycolipid-enriched microdomains (2010)
  • Author(s): Ohkawa Y, Miyazaki S, Hamamura K, Kambe M, Miyata M,Tajima O, Ohmi Y, Yamauchi Y, Furukawa K, Furukawa K.
  • Journal Title: J Biol Chem. Volume: 285 Issue: 35 Pages: 27213-27223
  • DOI: 10.1074/jbc.m109.087791
  • Peer Reviewed
• [Journal Article] Ganglioside GD3 enhances adhesion signals and augments malignant properties of melanoma cells by recruiting integrins to glycolipid-enriched microdomains. (2010)
  • Author(s): Ohkawa Y, Miyazaki S, Hamamura K, Kambe M, Miyata M, Tajima O, Ohmi Y, Yamauchi Y, Furukawa K, Furukawa K.
  • Journal Title: J Bid Chem Volume: 285 Pages: 27213-27223
  • Peer Reviewed
• [Journal Article] GM1/GD1b/GA1 synthase expression results in the reduced cancer phenotypes with modulation of composition and raft-localization of gangliosides in a melanoma cell line. (2010)
  • Author(s): Dong Y, Ikeda K, Hamamura K, Zhang Q, Kondo Y, Matsumoto Y, Ohmi Y, Yamauchi Y, Furukawa K, Taguchi R, Furukawa K.
  • Journal Title: Cancer Sci Volume: 101 Pages: 2039-2047
  • NAID: 10027831670
  • Peer Reviewed
• [Presentation] mTOR-mediated lipid sensing regulates the lipogenic phenotype in human cancer cells (2013)
  • Author(s): Yoshio Yamauchi
  • Organizer: The 5th Nagoya Global Retreat
  • Place of Presentation: 大府市
• [Presentation] Role of mTOR kinase in the lipogenic phenotype of human cancer cells (2012)
  • Author(s): 山内 祥生, 五十嵐 政智, 古 川 鋼 一
  • Organizer: 第85回日本生化学会大会
  • Place of Presentation: 福岡国際会議場, 福岡市
  • Year and Date: 2012-12-16
• [Presentation] Regulation of cholesterol homeostasis by ABCA1-dependent retrograde sterol transport (2012)
  • Author(s): 山内 祥生
  • Organizer: 第7回トランスポーター研究会年会
  • Place of Presentation: 京都大学, 京都市
  • Year and Date: 2012-06-09
• [Presentation] Miglustat and cyclodextrin promote lysosome-to- plasma membrane transport of disease-associated gangliosides in Niemann-Pick type C cells (2012)
  • Author(s): Yoshio Yamauchi
  • Organizer: Gordon Research Conference, Glycolipid & Sphingolipid Biology
  • Place of Presentation: Lucca, Italy
  • Year and Date: 2012-04-24
• [Presentation] Regulation of cholestrol homeostasis by ABCA1-dependent retrograde sterol transport (2012)
  • Author(s): 山内祥生
  • Organizer: 第７回トランスポーター研究会年会
  • Place of Presentation: 京都
  • Invited
• [Presentation] Miglustat and cyclodextrin promote lysosome-to-plasma membrane transport of diseased-associated gangliosides in Niemann-Pick type C cells. (2012)
  • Author(s): Yoshio Yamauchi
  • Organizer: Gordon Research Conference, Glycolipid & Sphingolipid Biology
  • Place of Presentation: Lucca, Italy
• [Presentation] Role of mTOR kinase in the lipogenic phenotype of human cancer cells (2012)
  • Author(s): 山内祥生
  • Organizer: 第85回日本生化学会大会
  • Place of Presentation: 博多
• [Presentation] Crucial role of the SREBP pathway in the proliferation of human melanoma cells (2012)
  • Author(s): 五十嵐政智
  • Organizer: 第85回日本生化学会大会
  • Place of Presentation: 博多
• [Presentation] The Niemann- Pick type C protein NPC1 regulates trafficking of disease-associated ganglioside from the lysosome to the plasma membrane (2011)
  • Author(s): Yoshio Yamauchi, Kosuke Yoshida, Ta-Yuan Chang, Keiko Furukawa, Koichi Furukawa
  • Organizer: 第34回日本分子生物学会年会
  • Place of Presentation: パシフィコ横浜, 横浜市
  • Year and Date: 2011-12-14
• [Presentation] The Niemann-Pick type C protein NPC1 regulates trafficking of disease-associated gangkiosides from the lysosome to the plasma membrane (2011)
  • Author(s): Yamauchi Y, Yoshida K, Chang T.Y, Furukawa K, Furukawa K.
  • Organizer: 第34回日本分子生物学会年会
  • Place of Presentation: パシフィコ横浜(神奈川県)
  • Year and Date: 2011-12-14
• [Presentation] Tumor antigen-activated lipogenic pathway is regulated via mTOR signaling : Crucial role of mTOR-SREBP pathway in the integrity of lipid rafts (2011)
  • Author(s): Yamauchi Y.
  • Organizer: Global COE Program The 3rd International Symposium -New Trends in Basic and Clinical Cancer Research for Innovative Therapy
  • Place of Presentation: ミッドランドホール(愛知県)
  • Year and Date: 2011-12-09
• [Presentation] ABCA1, membrane meso-domains, and sterol sensing (2011)
  • Author(s): Yoshio Yamauchi
  • Organizer: iCeMS Joint International Symposium ABC 2011 in Kyoto
  • Place of Presentation: 京都大学, 京都市
  • Year and Date: 2011-11-16
• [Presentation] ABCA1, sterol sensing, and membrane mesodomains (2011)
  • Author(s): Yamauchi Y.
  • Organizer: ABC2011 in Kyoto -ABC Proteins/Membrane Meso-domains/ES-iPS cells
  • Place of Presentation: 京都大学(京都府)(招待講演)
  • Year and Date: 2011-11-16
• [Presentation] Total analyses on the roles of cancer-associated gangliosides in malignant properties of melanomas (2011)
  • Author(s): Yoshio Yamauchi, Kazunori Hamamura, Yuki Ohkawa, Noboru Hashimoto, Yuhsuke Ohmi, Keiko Furukawa, Koichi Furukawa
  • Organizer: 70th Annual Meeting of the Japanese Cancer Association
  • Place of Presentation: 名古屋国際会議場, 名古屋市
  • Year and Date: 2011-10-04
• [Presentation] Total analyses on the roles of cancer-associated gangliosides in malignant properties of melanomas (2011)
  • Author(s): Yamauchi Y, Hamamura K, Ohkawa Y, Hashimoto N, Ohmi Y, Furukawa K, Furukawa K
  • Organizer: 第70回日本癌学会学術総会
  • Place of Presentation: 名古屋国際会議場(愛知県)(招待講演)
  • Year and Date: 2011-10-04
• [Presentation] Tumor antigen- activated lipogenic pathway is regulated via mTOR signaling : Crucial role of mTOR-SREBP pathway in the integrity of lipid rafts (2011)
  • Author(s): 山内 祥生, 古川 圭子, 浜村 和紀, 古川 鋼一
  • Organizer: 第84回日本生化学会大会
  • Place of Presentation: 国立京都国際会館, 京都市
  • Year and Date: 2011-09-24
• [Presentation] Tumor antigen-activated lipogenic pathway is regulated via mTOR signaling : Crucial role of mTOR-SREBP pathway in the integrity of lipid rafts (2011)
  • Author(s): 山内祥生、古川圭子、浜村和紀、古川鋼一
  • Organizer: 第84回日本生化学会大会
  • Place of Presentation: 国立京都国際会館(京都府)
  • Year and Date: 2011-09-24
• [Presentation] Positive feedback loop between PI3K-Akt-mTORC1 signaling and the lipogenic pathway boosts Akt signaling : Induction of the lipogenic pathway by a melanoma antigen (2011)
  • Author(s): Yoshio Yamauchi, Keiko Furukawa, Kazunori Hamamura, Koichi Furukawa
  • Organizer: The 30th Naito Conference on Membrane Dynamics and Lipid Biology [II] : Domains, Droplets and Diseases
  • Place of Presentation: シャトレーゼガトーキングダムサッポロ, 札幌市
  • Year and Date: 2011-06-30
• [Presentation] Positive feedback loop between PI3K-Akt-mTORC1 signaling and the lipogenic pathway boosts Akt signaling : Introduction of the lipogenic pathway by a melanoma antigen (2011)
  • Author(s): Yamauchi Y., Furukawa K, Hamamura K., Furukawa K.
  • Organizer: The 30^<th> Naito Conference on Membrane Dynamics and Lipid Biology [II] : Domains, Droplets and Diseases
  • Place of Presentation: シャトレーゼガトーキングダムサッポロ(北海道)
  • Year and Date: 2011-06-30
• [Presentation] Lysosomal accumulation of disease-associated gangliosides and small molecules that stimulate their lysosome-to-plasma membrane transport in Niemamm-Pick type C cells (2010)
  • Author(s): Yoshio Yamauchi, Kosuke Yoshida, Ta-Yuan Chang, Keiko Furukawa, Koichi Furukawa
  • Organizer: 第33回日本分子生物学会年会・第83回日本生化学会大会合同大会
  • Place of Presentation: 神戸国際会議場, 神戸市
  • Year and Date: 2010-12-07
• [Presentation] Lysosomal accumulation of disease-associated gangliosides and small molecules that stimulate their lysosome-to-plasma membrane transport in Niemann-Pick type C cells. (2010)
  • Author(s): Yamauchi Y, Yoshida K, Chang TY, Furukawa K, Furukawa K.
  • Organizer: 日本分子生物学会年会・日本生化学会大会合同大会
  • Place of Presentation: 神戸国際会議場(兵庫県)
  • Year and Date: 2010-12-07
• [Presentation] Accumulation of disease-related ganglosides in the late endosome/lysosome and small molecules that stimulates their transport to the plasma membrane in Niemann-Pick type C cells (2010)
  • Author(s): Yoshio Yamauchi, Kosuke Yoshida, Ta-Yuan Chang, Koichi Furukawa
  • Organizer: GlycoT 2010 Tokyo 7th International Symposium on Glycosyltransferases
  • Place of Presentation: KFC-Kokusai Fashion Center, 東京都墨田区
  • Year and Date: 2010-07-31