Functional analysis of amino acid transporter LAT1 in tumor endothelial cells

• Project/Area Number: 26430121
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Tumor biology
• Research Institution: Kyorin University
• Principal Investigator: Suehiro Jun-ichi 杏林大学, 医学部, 助教 (80572601)
• Co-Investigator(Renkei-kenkyūsha): WADA Youichiro 東京大学, アイソトープ総合センター, 教授 (10322033) ; SAKURAI Hiroyuki 杏林大学, 医学部, 教授 (00508294)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2016: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2015: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2014: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: がん微小環境 / アミノ酸トランスポーター / 腫瘍血管新生 / ＬＡＴ１ / 血管内皮細胞 / LAT1

Outline of Final Research Achievements

To elucidate the pathological roles of system L amino acid transporter LAT1 in tumor microenvironment, we examined in vitro endothelial function and in vivo tumor angiogenesis using LAT1 selective inhibitor, JPH203. JPH203 elicited amino acid deprivation stress and impaired endothelial cell growth, migration and tube formation in human umbilical vein endothelial cells. In mouse B16F10 melanoma xenograft model, JPH203 significantly inhibited tumor growth by attenuating angiogenesis. Taken together, these findings have provided the new insight in LAT1 function in tumor progression and showed the possibility of JPH203 as an angiogenesis inhibitor.

Research Products

• [Journal Article] A vascular permeability assay using an in vitro human microvessel model mimicking the inflammatory condition (2017)
  • Author(s): Joris Pauty, Ryo Usuba, Haruko Takahashi, Junichi Suehiro, Kanoko Fujisawa, Kiichiro Yano, Tomohiro Nishizawa, Yukiko T. Matsunaga
  • Journal Title: Nanotheranostics Volume: 1 Issue: 1 Pages: 103-113
  • DOI: 10.7150/ntno.18303
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Prostate Cancer Cells in Different Androgen Receptor Status Employ Different Leucine Transporters. (2017)
  • Author(s): Otsuki H, Kimura T, Yamaga T, Kosaka T, Suehiro JI, Sakurai H.
  • Journal Title: Prostate. Volume: 77 Issue: 2 Pages: 222-233
  • DOI: 10.1002/pros.23263
  • Peer Reviewed
• [Journal Article] Wolf-Hirschhorn syndrome candidate 1-like 1 epigenetically regulates nephrin gene expression. (2017)
  • Author(s): Ito Y, Katayama K, Nishibori Y, Akimoto Y, Kudo A, Kurayama R, Hada I, Takahashi S, Kimura T, Fukutomi T, Katada T, Suehiro J, Beltcheva O, Tryggvason K, Yan K.
  • Journal Title: Am J Physiol Renal Physiol. Volume: - Issue: 6 Pages: F1184-F1199
  • DOI: 10.1152/ajprenal.00305.2016
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Visualizing dynamics of angiogenic sprouting from a three-dimensional microvasculature model using stage-top optical coherence tomography (2017)
  • Author(s): Haruko Takahashi, Keisuke Kato, Kenji Ueyama, Masayoshi Kobayashi, Gunwoong Baik, Yasuhiro Yukawa, Jun-ichi Suehiro, Yukiko T. Matsunaga
  • Journal Title: Scientific Reports Volume: 7 Issue: 1 Pages: 42426-42426
  • DOI: 10.1038/srep42426
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Dynamically and epigenetically coordinated GATA/ETS/SOX transcription is indispensable for endothelial cell differentiation (2017)
  • Author(s): Kanki Y, Nakaki R, Shimamura T, Matsunaga T, Yamamizu K, Katayama S, Suehiro JI, Osawa T, Aburatani H, Kodama T, Wada Y, Yamashita JK, Minami T.
  • Journal Title: Nucleic Acids Research Volume: 印刷中 Issue: 8 Pages: 4344-4358
  • DOI: 10.1093/nar/gkx159
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Cross-enhancement of ANGPTL4 transcription by HIF1 alpha and PPAR beta/delta is the result of the conformational proximity of two response elements. (2014)
  • Author(s): Inoue T, Kohro T, Tanaka T, Kanki Y, Li G, Poh HM, Mimura I, Kobayashi M, Taguchi A, Maejima T, Suehiro JI, Sugiyama A, Kaneki K, Aruga H, Dong S, Stevens JF, Yamamoto S, Tsutsumi S, Fujita T, Ruan X, Aburatani H, Nangaku M, Ruan Y, Kodama T, Wada Y.
  • Journal Title: Genome Biology Volume: 15 Issue: 4
  • DOI: 10.1186/gb-2014-15-4-r63
  • Peer Reviewed / Open Access
• [Journal Article] Direct Evidence for Pitavastatin Induced Chromatin Structure Change in the KLF4 Gene in Endothelial Cells. (2014)
  • Author(s): Maejima T, Inoue T, Kanki Y, Kohro T, Li G, Ohta Y, Kimura H, Kobayashi M, Taguchi A, Tsutsumi S, Iwanari H, Yamamoto S, Aruga H, Dong S, Stevens JF, Poh HM, Yamamoto K, Kawamura T, Mimura I,
  • Journal Title: PLoS One. Volume: 9 Issue: 5 Pages: e96005-e96005
  • DOI: 10.1371/journal.pone.0096005
  • Peer Reviewed / Open Access
• [Journal Article] Genome-wide approaches reveal functional vascular endothelial growth factor (VEGF)-inducible nuclear factor of activated T cells (NFAT) c1 binding to angiogenesis-related genes in endothelium. (2014)
  • Author(s): Suehiro JI, Kanki Y, Makihara C, Schadler K, Miura M, Manabe Y, Aburatani H, Kodama T, Minami T
  • Journal Title: J Biol Chem Volume: 289 Issue: 42 Pages: 29044-59
  • DOI: 10.1074/jbc.m114.555235
  • Peer Reviewed / Open Access
• [Presentation] LAT1阻害時の血管内皮細胞におけるトランスクリプトーム解析 (2017)
  • Author(s): 末弘淳一，櫻井裕之
  • Organizer: 第90回日本薬理学会年会
  • Place of Presentation: 長崎
  • Year and Date: 2017-03-15
• [Presentation] アミノ酸トランスポーターLAT1阻害薬は血管内皮細胞増殖及び血管新生を抑制する. (2015)
  • Author(s): 末弘 淳一、田中 弦、木村 徹、櫻井 裕之.
  • Organizer: 第23回日本血管生物医学会学術集会
  • Place of Presentation: 神戸国際会議場
  • Year and Date: 2015-12-10
• [Remarks] 杏林大学医学部薬理学教室
  • URL: http://www.kyorin-u.ac.jp/univ/user/medicine/pharmaco/index.html
• [Remarks] 杏林大学医学部薬理学教室
  • URL: http://www.kyorin-u.ac.jp/univ/user/medicine/pharmaco/
• [Remarks] 杏林大学医学部薬理学教室
  • URL: http://www.kyorin-u.ac.jp/univ/faculty/medicine/education/labo/pharmacology/