Control of tumor progression by targeting the lipid rafts

• Project/Area Number: 24659150
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Single-year Grants
• Research Field: Pathological medical chemistry
• Research Institution: Osaka University
• Principal Investigator: ONEYAMA Chitose 大阪大学, 微生物病研究所, 准教授 (90373208)
• Project Period (FY): 2012-04-01 – 2014-03-31
• Project Status: Completed (Fiscal Year 2013)
• Budget Amount: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000); Fiscal Year 2013: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2012: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000)
• Keywords: ラフト / Src / がん

Research Abstract

In c-Src-induced transformation, we found that c-Src up-regulation perturbs sphingolipid/cholesterol-enriched membrane microdomains (lipid rafts) by activating ceramide synthesis and downregulation of cholesterol, resulting in promotion of c-Src translocation to focal adhesions. Inhibition of ceramide conversion into glucosylceramide promotes liberation of c-Src from microdomains, and inhibition of de novo ceramide synthesis restores the microdomain distribution of c-Src and suppresses c-Src-induced transformation. We tested whether alteration of the cholesterol content of lipid rafts in c-Src-dependent cell membranes affects tumor progression in vivo. We found simvastatin, a cholesterol synthesis inhibitor, lowered raft cholesterol content, promoted tumorigenicity of colon cancer cells. These results suggest that ceramide and cholesterol could be critical modifiers of tumor progression probably by modulating lipid rafts function.

Research Products

• [Journal Article] Roles of Raft-Anchored Adaptor Cbp/PAG1 in Spatial Regulation of c-Src Kinase. (2014)
  • Author(s): Saitou T, Kajiwara K, Oneyama C, Suzuki T, Okada M.
  • Journal Title: PLoS One. Volume: 9 Issue: 3 Pages: e93470-e93470
  • DOI: 10.1371/journal.pone.0093470
  • Peer Reviewed
• [Journal Article] The mTOR pathway controls cell proliferation by regulating the FoxO3a transcription factor via SGK1 kinase (2014)
  • Author(s): Mori S, Nada S, Kimura H, Tajima S, Takahashi Y, Kitamura A, Oneyama C, Okada M.
  • Journal Title: PLos ONE Volume: 9(2) Issue: 2 Pages: e88891-e88891
  • DOI: 10.1371/journal.pone.0088891
  • Peer Reviewed / Open Access
• [Journal Article] c-Src-induced activation of ceramide metabolism impairs membrane microdomains and promotes malignant progression by facilitating the translocation of c-Src to focal adhesions (2014)
  • Author(s): Kajiwara K, Yamada T, Bamba T, Fukusaki E, Imamoto F, Okada M, Oneyama C.
  • Journal Title: Biochem J. Volume: 458(1) Issue: 1 Pages: 81-93
  • DOI: 10.1042/bj20130527
  • Peer Reviewed / Open Access
• [Journal Article] Roles of Raft-Anchored Adaptor Cbp/PAG1 in Spatial Regulation of c-Src Kinase. (2014)
  • Author(s): Saitou T, Kajiwara K, Oneyama C, Suzuki T, Okada M.
  • Journal Title: PLoS One Volume: 9(3)
  • Peer Reviewed
• [Journal Article] The lysosomal signaling anchor p18/LAMTOR1 controls epidermal development by regulating lysosome-mediated catabolic processes (2013)
  • Author(s): Soma-Nagae T, Nada S, Kitagawa M, Takahashi Y, Mori S, Oneyama C, Okada M
  • Journal Title: J Cell Sci 2013 Volume: 126(Pt 16) Pages: 3575-84
  • DOI: 10.1242/jcs.121913
  • Peer Reviewed
• [Journal Article] Identification of a new interaction mode between the Src homology 2 domain of C-terminal Src kinase (Csk) and Csk-binding protein/phosphoprotein associated with glycosphingolipid microdomains (2013)
  • Author(s): Tanaka H, Akagi K, Oneyama C, Tanaka M, Sasaki Y, Kanou T, Lee YH, Yokogawa D, Dobenecker MW, Nakagawa A, Okada M, Ikegami T
  • Journal Title: J Biol Chem 2013 Volume: 288(21) Issue: 21 Pages: 15240-54
  • DOI: 10.1074/jbc.m112.439075
  • NAID: 120006770869
  • Peer Reviewed
• [Journal Article] Involvement of gangliosides in the process of Cbp/PAG phosphorylation by Lyn in developing cerebellar growth cones (2013)
  • Author(s): Sekino-Suzuki N, Yuyama K, Yamamoto T. (10名)
  • Journal Title: J Neurochem Volume: Vol.124 Issue: 4 Pages: 514-522
  • DOI: 10.1111/jnc.12040
  • Peer Reviewed
• [Journal Article] MicroRNA-mediated upregulation of integrin-linked kinase promotes Src-induced tumor progression (2012)
  • Author(s): Oneyama C, Morii E, Okuzaki D, Takahashi Y, Ikeda J, Wakabayashi N, Akamatsu H, Tsujimoto M, Nishida T, Aozasa K, Okada M
  • Journal Title: Oncogene 2012 Volume: 31(13) Issue: 13 Pages: 1623-35
  • DOI: 10.1038/onc.2011.367
  • Peer Reviewed
• [Presentation] Srcチロシンキナーゼの脂質ラフトによるがん化シグナル制御 (2014)
  • Author(s): 小根山千歳
  • Organizer: 大阪大学蛋白質研究所セミナー
  • Year and Date: 2014-03-15
• [Presentation] 脂質ラフトを介するc-Srcがん化シグナルの制御 (2014)
  • Author(s): 小根山千歳
  • Organizer: 岡山大学大学院医歯薬学総合研究科
  • Year and Date: 2014-03-07
• [Presentation] Hisataka Sabe「Mechanisms by which p53 alterations generate GEP100-Arf6-AMAP1 pathway as a mesenchymal invasion machinery to be activated by RTK-ligands and TGF-beta1」 (2013)
  • Author(s): Ari Hashimoto, Shigeru Hashimoto, Yasuhito Onodera, Tsukasa Oikawa, Chitose Oneyama, RumikoKinoshita, Jin-Min Nam, Mishie Tanino, Hirokzu Sugino, Ayumu Yoshikawa, Yutaro Otsuka, Haruka Handa, Masanao Yoshino, Hiroki Sato, Satoshi Fukuda, Shinya Tanaka, Hiroki Shirato, Yoichi Ito, Masato Okada
  • Organizer: 第36回日本分子生物学会年会
  • Year and Date: 2013-12-04
• [Presentation] Ferを介したc-Srcによるがん形質発現 (2013)
  • Author(s): 小根山千歳、吉川由利子、飯野琢也、月田早智子、岡田雅人
  • Organizer: 第36回日本分子生物学会年会
  • Year and Date: 2013-12-04
• [Presentation] C末端SrcキナーゼのSH2ドメインとCbp/PAGとの間の新しい相互作用様式の発見 (2013)
  • Author(s): 田中宏明、赤木謙一、小根山千歳、田中雅千、佐々木優一、狩野孝、Lee Young-Ho、横川大輔、Dobenecker Marc-Werner、中川敦史、岡田雅人、池上貴久
  • Organizer: 第36回日本分子生物学会年会
  • Year and Date: 2013-12-03
• [Presentation] Srcによるがん形質発現メカニズムの再考 (2013)
  • Author(s): 小根山千歳
  • Organizer: 奈良先端技術大学未来開拓コロキウム(奈良)
  • Year and Date: 2013-10-22
• [Presentation] Regulation of c-Src-induecd oncogenic pathways via membrane microdomain (2012)
  • Author(s): 吉川由利子、小根山千歳、飯野琢也、岡田雅人
  • Organizer: 第35回日本分子生物学会年会
  • Year and Date: 2012-12-14
• [Presentation] Src-induced ceramide overexpression promotes tumor progression by perturbing membrane microdomains (2012)
  • Author(s): 梶原健太郎、小根山千歳、今本文男、岡田雅人
  • Organizer: 第35回日本分子生物学会年会
  • Year and Date: 2012-12-11
• [Presentation] 細胞膜ミクロドメイン"脂質ラフト"を介したc-Srcがん形質発現シグナルの制御 (2012)
  • Author(s): 吉川由利子、小根山千歳、飯野琢也、岡田雅人
  • Organizer: 第71回日本癌学会学術総会
  • Year and Date: 2012-09-19
• [Presentation] Lipid raftによるがん化制御 (2012)
  • Author(s): 吉川由利子、小根山千歳、岡田雅人
  • Organizer: 第4回シグナルネットワーク研究会
  • Year and Date: 2012-05-19
• [Presentation] Srcチロシンキナーゼの脂質ラフトによるがん化シグナル制御
  • Author(s): 小根山千歳
  • Organizer: 大阪大学蛋白質研究所セミナー
  • Place of Presentation: 大阪
  • Invited
• [Presentation] 脂質ラフトを介するc-Srcがん化シグナルの制御
  • Author(s): 小根山千歳
  • Organizer: 岡山大学大学院医歯薬学総合研究科特別セミナー
  • Place of Presentation: 岡山
  • Invited
• [Presentation] Srcによるがん形質発現メカニズムの再考
  • Author(s): 小根山千歳
  • Organizer: 奈良先端技術大学未来開拓コロキウム
  • Place of Presentation: 奈良
  • Invited
• [Presentation] C末端SrcキナーゼのSH2ドメインとCbp/PAGとの間の新しい相互作用様式の発見
  • Author(s): 田中宏明、赤木謙一、小根山千歳、田中雅千、佐々木優一、狩野孝、Lee Young-Ho、横川大輔、Dobenecker Marc-Werner、中川敦史、岡田雅人、池上貴久
  • Organizer: 第36回日本分子生物学会年会
  • Place of Presentation: 神戸
• [Presentation] Mechanisms by which p53 alterations generate GEP100-Arf6-AMAP1 pathway as a mesenchymal invasion machinery to be activated by RTK-ligands and TGF-beta1
  • Author(s): Ari Hashimoto, Shigeru Hashimoto, Yasuhito Onodera, Tsukasa Oikawa, Chitose Oneyama, Rumiko Kinoshita, Jin-Min Nam, Mishie Tanino, Hirokzu Sugino, Ayumu Yoshikawa, Yutaro Otsuka, Haruka Handa, Masanao Yoshino, Hiroki Sato, Satoshi Fukuda, Shinya Tanaka, Hiroki Shirato, Yoichi Ito, Masato Okada, Hisataka Sabe
  • Organizer: 第36回日本分子生物学会年会
  • Place of Presentation: 神戸
• [Presentation] Ferを介したc-Srcによるがん形質発現
  • Author(s): 小根山千歳、吉川由利子、飯野琢也、月田早智子、岡田雅人
  • Organizer: 第36回日本分子生物学会年会
  • Place of Presentation: 神戸
• [Presentation] Lipid raftによるがん化制御
  • Author(s): 吉川由利子、小根山千歳、岡田雅人
  • Organizer: 第４回シグナルネットワーク研究会
  • Place of Presentation: 大阪
• [Presentation] 細胞膜ミクロドメイン“脂質ラフト”を介したc-Srcがん形質発現シグナルの制御
  • Author(s): 吉川由利子、小根山千歳、飯野琢也、岡田雅人
  • Organizer: 第７１回日本癌学会学術総会
  • Place of Presentation: 北海道
• [Presentation] Src-induced ceramide overexpression promotes tumor progression by perturbing membrane microdomains
  • Author(s): 梶原健太郎、小根山千歳、今本文男、岡田雅人
  • Organizer: 第35回日本分子生物学会年会
  • Place of Presentation: 福岡
• [Presentation] Regulation of c-Src-induecd oncogenic pathways via membrane microdomain
  • Author(s): 吉川由利子、小根山千歳、飯野琢也、岡田雅人
  • Organizer: 第35回日本分子生物学会年会
  • Place of Presentation: 福岡
• [Remarks]
  • URL: http://www.biken.osaka-u.ac.jp/biken/oncogene/index.htm
• [Remarks] 大阪大学微生物病研究所 発癌制御研究分野
  • URL: http://www.biken.osaka-u.ac.jp/biken/oncogene/index.htm