2003 Fiscal Year Annual Research Report

リバースオンコロジー;がん胎児性LAT1抑制薬による遺伝子変化の網羅的解析

Research Project

Project/Area Number	15023251
Research Institution	Kyorin University
Principal Investigator	遠藤仁杏林大学, 医学部, 教授 (20101115)
Co-Investigator(Kenkyū-buntansha)	入部雄司杏林大学, 医学部, 助手 (20348618) 金井好克杏林大学, 医学部, 教授 (60204533)
Keywords	中性アミノ酸トランスポーター / LAT1 / LAT2 / LAT1抑制薬 / BCH / トランスポーター抑制薬 / 癌治療法 / 必須アミノ酸
Research Abstract	がん細胞では、上昇した細胞内代謝を保障するために、糖やアミノ酸の取り込みが亢進している。特に必須アミノ酸トランスポーターは、がん細胞増殖の律速段階の一つを形成している。その主要な要素であるがん胎児性中性アミノ酸トランスポーター(LAT1)とその活性化因子(4F2hc)は、すでに種々のがん細胞に発現が亢進し、その増殖に重要な役割を果たしていることが示されている。本研究では、ヒト咽頭がん由来のHEp-2細胞を用いて、LAT1と4F2hcの発現を遺伝子とタンパクレベルで検討し、両者の高い発現を認めた。HEp-2細胞の増殖はLAT1/4F2hc系の抑制物質のBCHと同時に比較したシスプラチン(CDDP)によっても抑制を確認した。DNAマイクロアレーにより2倍以上に発現が増加した遺伝子の数はBCHでは45、CDDPにより374、2倍以上低下した遺伝子はBCHで56、CDDPで395、と明らかな差異が認められた。これらの変化する程度はBCHによる方がCDDPのそれよりも明らかに低い事が認められた。これは、BCHが特定の機能性タンパク質を特異的な標的としているためと考えられる。以上より、がん細胞の増殖を抑制する際の標的分子数が遺伝子全体の定性・定量的変化に反映される事が判明したので、遺伝子変化のプロフィールにより抗がん薬の作用機序を推定する事が可能になった。本研究によるリバースオンコロジーのアプローチは、現存するヒト由来株化がん細胞と現存する抗がん薬の量的、時間的組み合せの実験結果をデータベース化し、網羅的遺伝子解析結果と臨床効果の比較を通し、より有効性の高い抗がん薬の創製を目指した研究へと発展される必要がある。

Research Products
(21 results)

All Other

All Publications (21 results)

[Publications] Enomoto, A., Kimura, H., Chairoungdua, Okubo, M., Yamada, K., Hosoyamada, M., Shibasaki, T., Endou, H.: "Cadmium transport by human Nramp 2 expressed in Xenopus laevis oocytes."Toxicol.Applied Pharmacol.. 187. 162-167 (2003)
[Publications] Enomoto, A., Takeda, M., Taki, K., Takayama, F, Noshiro, R., Niwa, T., Endou, H.: "Interactions of human organic anion as well as carion transporters with indoxyl sulfate."Euro.J.Pharmacol.. 466. 13-20 (2003)
[Publications] Satoh, H., Moriyama, N., Hara, C., Yamada, H., Horita, S., Kunimi, M., Tsukamoto, K., Iso-o, N., Inatomi, J., Kawakami, H., Kudo, A., Endou, H., Igarashi, T., Goto, A., Fujita T, Seki G: "Localization of Na^+-HCO_3^-cotransporter (NBC-1)variants in rat and human pancreas."Am.J.Physiol.Cell Physiol.. 284. C729-C737 (2003)
[Publications] Kanai, Y., Endou, H.: "Functional properties of multispecific amino acid transporters and their implications to transporter-mediated toxicity."J.Toxicol.Sci.. 28. 1-17 (2003)
[Publications] Hasegawa, M., Kusuhara, H., Endou, H., Sugiyama, Y.: "Contribution of organic anion transporters to the renal uptake of anionic compounds and nucleoside derivatives in rat."J.Pharmacol.Exp.Ther.. 305(3). 1087-1097 (2003)
[Publications] Jutabha, P., Kanai, Y., Hosoyamada, M., Chairoungdua, A., Kim, D.K., Iribe, Y., Babu, E., Kim, J.Y., Anzai, N., Chatsudthipong, V., Endou, H.: "Identification of a novel voltage-driven organic anion transporter present at apical membrane of renal proximal tubule."J.Biol.Chem.. 278(30). 28930-27938 (2003)
[Publications] Hosoya K, Tomi M, Ohtsuki S, Takanaga H, Saeki S, Kanai Y, Endou H, Naito M, Tsuruo T, Terasaki T: "Enhancement of L-cystine transport activity and its relation to xCT gene induction at the blood-brain barrier by diethyl maleate treatment."J Pharmacol Exp Ther.. 302(1). 225-231 (2003)
[Publications] Tanaka M, Itoh K, Matsushita K, Matsushita K, Wakita N, Adachi M, Nonoguchi H, Kitamura K, Hosoyamada M, Endou H, Tomita K.: "Two male siblings with hereditary renal hypouricemia and exercise-induced ARF."Am J Kidney Dis.. 42(6). 1287-1292 (2003)
[Publications] Babu E, Kanai Y, Chairoungdua A, Kim do K, Iribe Y, Tangtrongsup S, Jutabha P, Li Y, Ahmed N, Sakamoto S, Anzai N, Nagamori S, Endou H.: "Identification of a novel system L amino acid transporter structurally distinct from heterodimeric amino acid transporters."J Biol Chem.. 278(44). 43838-43845 (2003)
[Publications] Kim GH, Na KY, Kim SY, Joo KW, Oh YK, Chae SW, Endou H, Han JS.: "Up-regulation of organic anion transporter 1 protein is induced by chronic furosemide or hydrochlorothiazide infusion in rat kidney."Nephrol Dial Transplant.. 18(8). 1505-1511 (2003)
[Publications] Alebouyeh M, Takeda M, Onozato ML, Tojo A, Noshiro R Hasannejad H, Inotaomi J, Narikaw S, Huang XL, Khamdang, Anzai N, Endou H: "Expression of human organic anion-transorters in the choroid plexus and their interactions with neurotransmitter metabolites."J Pharmachol sci.. 93. 430-436 (2003)
[Publications] Yoon JH, Kim YB, Kanai Y, Endou H, Kim DK: "Sequential Increases in 4F2hc expression during DMBA-induced hamster buccal pouch cacinogenesis."Anticancer Res.. 23. 3877-3882 (2003)
[Publications] Tanaka M., Itoh K., Matsushita K, Matsushita K, Wakita N, Adachi M, Nonoguchi H, Kitamura K, Hosoyamada M, Endou H., Tomita K.: "Two male siblings with hereditary renal hypouricemia and exercise-induced ARF."Am.J.Kidney Des.. 42(6). 1287-1292 (2003)
[Publications] Takeda M, Norshio R, Onozato ML, Tojo A, Hasannejad H, Hang XL, Narikawa S, Endou H.: "Evidence for a role of human organic anion transporters in the muscular side effects of HMG-GoA reductase inhibitors."Eur.J.Pharmacol.. 483. 133-138 (2004)
[Publications] Sakata T, Anzai N, Shin HJ, Norhiro R, Hirata T, Yokoyama H, Kanai Y, Endou H.: "Novel single nucleotide polymorphisms of organic cation transporter 1 (SLC22A1) affecting transport functions."Biochem Biophys Res Comm.. 313. 789-793 (2004)
[Publications] Hasannejad H, Takeda M, Taki K, Jung SH, Babu E, Jutabha P, Khamdang S, Aleboyeh M, Onodera ML, Tojo A, Enomoto A, Anzai N, Narikawa S, Huang XL, Niwa T, Endou H.: "Interactions of human organic anion transporters with diuretics."J Pharmacol Exp Ther.. 308(3). 1021-1029 (2004)
[Publications] Khamdan S, Takeda M, shimoda M, Noshiro Ri, Narikawa S, Huang XL, Enomoto A, Piyachaturawat P, Hitoshi E: "Interactions of human-and rat-organic anion transporters with pravastatih and cimetidine."J Pharmachol sci.. 94. 197-202 (2004)
[Publications] Ekaratanawong S, Anzai N, Jutabha P, Miyazaki H, Noshiro R, Takeda M, Kanai M, Sophasan S, Endou H: "Human organic anion transporter 4 is a renal apical organic anion/dicarboxylate exchanger in the proximal tubules."Biochem Biophys Res Comm.. 94. 297-304 (2004)
[Publications] Verrey F, Closs EI, Wagner CA, Palacin M, Endou H, Kanai Y.: "CATs and HATs : the SLC7 family of amino acid transporters."Pflugers Arch.. 447. 532-542 (2004)
[Publications] Koepsell H, Endou H.: "The SLC22 drug transporter family."Pflugers Arch.. 447. 666-676 (2004)
[Publications] 安西尚彦, 宮崎博喜, 遠藤仁: "細胞内結合タンパク質による膜輸送体機能制御 Annual Review腎臓2004、伊藤克己等編"中外医学社. 6 (2004)

2003 Fiscal Year Annual Research Report

リバースオンコロジー;がん胎児性LAT1抑制薬による遺伝子変化の網羅的解析

Principal Investigator

遠藤 仁 杏林大学, 医学部, 教授 (20101115)

Research Products

[Publications] Enomoto, A., Kimura, H., Chairoungdua, Okubo, M., Yamada, K., Hosoyamada, M., Shibasaki, T., Endou, H.: "Cadmium transport by human Nramp 2 expressed in Xenopus laevis oocytes."Toxicol.Applied Pharmacol.. 187. 162-167 (2003)

[Publications] Enomoto, A., Takeda, M., Taki, K., Takayama, F, Noshiro, R., Niwa, T., Endou, H.: "Interactions of human organic anion as well as carion transporters with indoxyl sulfate."Euro.J.Pharmacol.. 466. 13-20 (2003)

[Publications] Kanai, Y., Endou, H.: "Functional properties of multispecific amino acid transporters and their implications to transporter-mediated toxicity."J.Toxicol.Sci.. 28. 1-17 (2003)

[Publications] Hasegawa, M., Kusuhara, H., Endou, H., Sugiyama, Y.: "Contribution of organic anion transporters to the renal uptake of anionic compounds and nucleoside derivatives in rat."J.Pharmacol.Exp.Ther.. 305(3). 1087-1097 (2003)

[Publications] Tanaka M, Itoh K, Matsushita K, Matsushita K, Wakita N, Adachi M, Nonoguchi H, Kitamura K, Hosoyamada M, Endou H, Tomita K.: "Two male siblings with hereditary renal hypouricemia and exercise-induced ARF."Am J Kidney Dis.. 42(6). 1287-1292 (2003)

[Publications] Kim GH, Na KY, Kim SY, Joo KW, Oh YK, Chae SW, Endou H, Han JS.: "Up-regulation of organic anion transporter 1 protein is induced by chronic furosemide or hydrochlorothiazide infusion in rat kidney."Nephrol Dial Transplant.. 18(8). 1505-1511 (2003)

[Publications] Yoon JH, Kim YB, Kanai Y, Endou H, Kim DK: "Sequential Increases in 4F2hc expression during DMBA-induced hamster buccal pouch cacinogenesis."Anticancer Res.. 23. 3877-3882 (2003)

[Publications] Tanaka M., Itoh K., Matsushita K, Matsushita K, Wakita N, Adachi M, Nonoguchi H, Kitamura K, Hosoyamada M, Endou H., Tomita K.: "Two male siblings with hereditary renal hypouricemia and exercise-induced ARF."Am.J.Kidney Des.. 42(6). 1287-1292 (2003)

[Publications] Takeda M, Norshio R, Onozato ML, Tojo A, Hasannejad H, Hang XL, Narikawa S, Endou H.: "Evidence for a role of human organic anion transporters in the muscular side effects of HMG-GoA reductase inhibitors."Eur.J.Pharmacol.. 483. 133-138 (2004)

[Publications] Sakata T, Anzai N, Shin HJ, Norhiro R, Hirata T, Yokoyama H, Kanai Y, Endou H.: "Novel single nucleotide polymorphisms of organic cation transporter 1 (SLC22A1) affecting transport functions."Biochem Biophys Res Comm.. 313. 789-793 (2004)

[Publications] Hasannejad H, Takeda M, Taki K, Jung SH, Babu E, Jutabha P, Khamdang S, Aleboyeh M, Onodera ML, Tojo A, Enomoto A, Anzai N, Narikawa S, Huang XL, Niwa T, Endou H.: "Interactions of human organic anion transporters with diuretics."J Pharmacol Exp Ther.. 308(3). 1021-1029 (2004)

[Publications] Khamdan S, Takeda M, shimoda M, Noshiro Ri, Narikawa S, Huang XL, Enomoto A, Piyachaturawat P, Hitoshi E: "Interactions of human-and rat-organic anion transporters with pravastatih and cimetidine."J Pharmachol sci.. 94. 197-202 (2004)

[Publications] Ekaratanawong S, Anzai N, Jutabha P, Miyazaki H, Noshiro R, Takeda M, Kanai M, Sophasan S, Endou H: "Human organic anion transporter 4 is a renal apical organic anion/dicarboxylate exchanger in the proximal tubules."Biochem Biophys Res Comm.. 94. 297-304 (2004)

[Publications] Verrey F, Closs EI, Wagner CA, Palacin M, Endou H, Kanai Y.: "CATs and HATs : the SLC7 family of amino acid transporters."Pflugers Arch.. 447. 532-542 (2004)

[Publications] Koepsell H, Endou H.: "The SLC22 drug transporter family."Pflugers Arch.. 447. 666-676 (2004)

[Publications] 安西尚彦, 宮崎博喜, 遠藤 仁: "細胞内結合タンパク質による膜輸送体機能制御 Annual Review腎臓2004、伊藤克己等編"中外医学社. 6 (2004)

遠藤仁杏林大学, 医学部, 教授 (20101115)

[Publications] 安西尚彦, 宮崎博喜, 遠藤仁: "細胞内結合タンパク質による膜輸送体機能制御 Annual Review腎臓2004、伊藤克己等編"中外医学社. 6 (2004)