Molecular basis for the inhibition of hypoxia-induced apoptosis by thymidine phosphorylase

• Project/Area Number: 20790139
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Single-year Grants
• Research Field: Medical pharmacy
• Research Institution: Kagoshima University
• Principal Investigator: IKEDA Ryuji Kagoshima University, 医学部・歯学部附属病院, 薬剤師 (50398278)
• Project Period (FY): 2008 – 2009
• Project Status: Completed (Fiscal Year 2009)
• Budget Amount: ¥2,600,000 (Direct Cost: ¥2,000,000、Indirect Cost: ¥600,000); Fiscal Year 2009: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2008: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: Thymidine Phosphorylase / 2-Deoxy-D-ribose / Hypoxia-inducible factor -1 / チミジンホスホリラーゼ / 2-デオキシ-D-リボース / HIF-1α / プロリン水酸化酵素 / ユビキチン-プロテアソーム / Fe^<2+> / Von-HipPel Lindau遺伝子 / ユビキチンプロテアソーム

Research Abstract

An angiogenic factor, platelet-derived endothelial cell growth factor/thymidine phosphorylase (PD-ECGF/TP), stimulates the chemotaxis of endothelial cells and confers resistance to apoptosis induced by hypoxia. TP and 2-deoxy-D-ribode, a degradation product of thymidine generated by TP enzymatic activity, inhibited the upregulation of hypoxia-inducible factor (HIF) 1α induced by hypoxia. We investigated the molecular basis for the suppressive effect of TP and 2-deoxy-D-ribose on the upregulation of HIF-1α. 2-Deoxy-D-ribose enhanced interaction of HIF-1α and pVHL under hypoxic condition. 2-Deoxy-D-ribose did not affect the expression of HIF-1α, prolyl hydroxylase (PHD)1/2/3 and VHL mRNA. 2-Deoxy-D-ribose also enhanced interaction of HIF-1α and PHD2 under hypoxic condition. Further study is needed to elucidate the mechanism about the augmented interaction of HIF-1α with pVHL and PHD2.

Research Products

• [Journal Article] SUVmax of FDG-PET correlates with the effects of neoadjuvant chemoradiotherapy for oral squamous cell carcinoma (2010)
  • Author(s): Miyawaki, A., Ikeda, R., Hijioka, H., Ishida, T., Ushiyama, M., Nozoe, E., Nakamura, N.
  • Journal Title: Oncol. Rep. 23 Pages: 1205-1212
• [Journal Article] The role of thymidine phosphorylase in the induction of early growth response protein-1 and thrombospondin-1 by 5-fluorouracil in human cancer carcinoma cells (2010)
  • Author(s): Matsushita, S., Ikeda, R., Nishizawa Y., Che X.F., Furukawa T., Miyadera K., Tabata S., Ushiyama M., Tajitsu Y., Yamamoto M., Takeda Y., Minami K., Mataki H., Kanzaki, T., Yamada K., Kanekura T., Akiyama S.
  • Journal Title: Int. J. Oncol. 36 Pages: 1193-1200
• [Journal Article] Major vault protein forms complexes with hypoxia-inducible factor (HIF)-1α and reduces HIF-1α level in ACHN human renal adenocarcinoma cells (2010)
  • Author(s): Iwashita K., Ikeda R., Takeda Y., Sumizawa T., Furukawa T., Yamaguchi T., Akiyama S., Yamada K.
  • Journal Title: Cancer Sci. 101 Pages: 920-926
  • NAID: 10026590870
• [Journal Article] Major vault protein forms complexes with hypoxia-inducible factor (HIF)-1α and reduces HIF-1α level in ACHN human renal adenocarcinoma cells (2010)
  • Author(s): Iwashita K., Ikeda R., Takeda Y., Sumizawa T., Furukawa T., Yamaguchi T., Akiyama S., Yamadak.
  • Journal Title: Cancer Science 101 Pages: 920-926
  • NAID: 10026590870
  • Peer Reviewed
• [Journal Article] The role of thymidine phosphorylase in the induction of early growth response protein-1 and thrombospondin-1 by 5-fluorouracil in human cancer carcinoma cells (2010)
  • Author(s): Matsushita, S., lkeda, R., Nishizawa Y., Che X. F., Furukawa T., Miyadera K., Tabata S., Ushiyama M., Tajitsu Y., Yamamoto M,. Takeda Y., Minami K., Mataki H., Kanzaki, T., Yamada K., Kanekura T., Akiyama S.
  • Journal Title: Internatinal Journal of Oncology 36 Pages: 1193-1200
  • Peer Reviewed
• [Journal Article] SUVmax of FDG-PET correlates with the effects of neoadjuvant chemoradiotherapy for oral squamous cell carcinoma (2010)
  • Author(s): Miyawaki, A., Ikeda, R., Hijioka, H., Ishida, T., Usiyama, M.., Nozoe, E., Nakamura, N.
  • Journal Title: Oncology Reports 23 Pages: 1205-1212
  • Peer Reviewed
• [Journal Article] Adverse effects of superselective intra-arterial infusion chemotherapy in patients with oral cancer (2009)
  • Author(s): Ushiyama, M., Ikeda, R., Yamaguchi, H., Miyawaki, A., Nitta, T., Yamaguchi, T., Matsumoto, K., Shimodouzono, Y., Furukawa, T., Akiyama, S., Nakamura N., Yamada, K.
  • Journal Title: Journal of Applied Therapeutic Research 7 Pages: 58-64
• [Journal Article] Stability of hospital preparations of Azunol Water Gargles for pain relief in oral cancer patients with oral mucositis (2009)
  • Author(s): Ushiyama, M., Ikeda, R., Nitta, T., Tazitsu, Y., Miyawaki, A., Nishizawa, Y., Yamaguchi, T., Yamaguchi, H., Akatsuka, C., Shimodouzono, Y., Ushinohama, K., Sugawara, H., Sugihara, K., Nakamura, N., Takeda, Y., Yamada, K.
  • Journal Title: Cancer Therapy 7 Pages: 277-281
• [Journal Article] Enhanced platelet responsiveness due to chilling and its relation to CD40 ligand level and platelet-leukocyte aggregate formation (2009)
  • Author(s): Ayukawa, O., Nakamura, K., Kariyazono, H., Ikeda, R., Arima, J., Shinkawa, T., Iwase, H., Sakata, R., Yamada, K.
  • Journal Title: Blood Coagul. Fibrinolysis 20 Pages: 176-184
• [Journal Article] Contactin-associated protein (Caspr) 2 interacts with carboxypeptidase E in the CNS (2009)
  • Author(s): Oiso, S., Takeda, Y., Futagawa, T., Miura, T., Kuchiiwa, S., Nishida, K., Ikeda, R., Kariyazono, H., Watanabe, K., Yamada, K.
  • Journal Title: J. Neurochem. 109 Pages: 158-167
• [Journal Article] Copper transport systems are involved in multidrug resistance and drug transport (2009)
  • Author(s): Furukawa, T., Komatsu, M., Ikeda, R., Tsujikawa, K., Akiyama, S.
  • Journal Title: Curr. Med. Chem. 15 Pages: 3268-3278
• [Journal Article] Enhanced platelet responiveness due to chilling and its relation to CD40 ligand level and platelet-leukocyte aggregate formation (2009)
  • Author(s): Ayukawa, O., Nakamura, K., Kariyazono, H., lkeda, R., Arima, J., Shinkawa, T., lwase, H., Sakata, R., Yamada, K.
  • Journal Title: Blood Coagulation and Fibrinolysis 20 Pages: 176-184
  • Peer Reviewed
• [Journal Article] Stabiligy of hospital preparations of Azunol Water Gargles for pain relief in oral cancer patients with oral mucositis (2009)
  • Author(s): Ushiyama, M., lkeda, R., Nitta, T., Tazitsu , Y., Miyawaki, A., Nishizawa, Y., Yamaguchi, T., Yamaguxhi, H., Akatsuka, C., Shimodouzono, Y., Ushinohama, K., Sugawara, H., Sugihara, K., Nakamura, N., Takeda, Y., Yamada, K.
  • Journal Title: Cancer Therapy 7 Pages: 277-281
  • Peer Reviewed
• [Journal Article] Adverse effects of superselective intra-arterial infusion chemotherapy in patients with oral cancer (2009)
  • Author(s): Ushiyama, M., Ikeda, R., Yamaguchi, H., Miyawaki, A., Nitta, T., Yamguchi, T., Matsumoto, K., Shimodouzono, Y., Furkawa, T., Akiyama, S., Nakamura N., Yamada, K.
  • Journal Title: Journal of Applied Therapeutic Research 7 Pages: 58-64
  • Peer Reviewed
• [Journal Article] Copper transport systems are involved in multidrug resistance and drug transport (2009)
  • Author(s): Furukawa T, Komatsu M, Ikeda R, Tsujikawa K, Akiyama S
  • Journal Title: Curr. Med. Chem. 15 Pages: 3268-3278
  • Peer Reviewed
• [Journal Article] Contactin-associated protein(Caspr)2 interacts with carboxypeptidase E in the CNS (2009)
  • Author(s): Oiso S, Takeda Y, Futagawa T, Miura T, Kuchiiwa S, Nish ida K, Ikeda R, Kariyazono H, Watanabe K, Yamada K
  • Journal Title: J. Neurochem. 109 Pages: 158-167
  • Peer Reviewed
• [Journal Article] Down regulation of c-Myc and induction of an angiogenesis inhibitor, thrombospondin-1, by 5-FU in human colon cancer KM12C cells (2008)
  • Author(s): Zhao, H.Y., Ooyama, A., Yamamoto, M., Ikeda, R., Haraguchi, M., Tabata, S., Furukawa, T., Che, X.F., Iwashita, K., Oka, T., Fukushima, M., Nakagawa, M., Ono, M., Kuwano, M., Akiyama, S.
  • Journal Title: Cancer Lett. Pages: 156-163
• [Journal Article] Molecular basis for the induction of an angiogenesis inhibitor, thrombospondin-1, by 5-fluorouracil (2008)
  • Author(s): Zhao, H.Y., Ooyama, A., Yamamoto, M., Ikeda, R., Haraguchi, M., Tabata, S., Furukawa, T., Che, X.F., Zhang, S., Oka, T., Fukushima, M., Nakagawa, M., Ono, M., Kuwano, M., Akiyama, S.
  • Journal Title: Cancer Res. 68 Pages: 7035-7041
• [Journal Article] Hyperosmotic stress up-regulates the expression of major vault protein in SW620 human colon cancer cells (2008)
  • Author(s): Ikeda, R., Iwashita, K., Sumizawa, T., Beppu, S., Tabata, S., Tajitsu, Y., Shimamoto, Y., Yoshida, K., Furukawa, T., Che, X.F., Yamaguchi, T., Ushiyama, M., Miyawaki, A., Takeda, Y., Yamamoto, M., Zhao, H.Y., Shibayama, Y., Yamada, K., Akiyama, S.
  • Journal Title: Exp. Cell Res. 314 Pages: 3017-3026
• [Journal Article] Hyperosmotic stress up-regulates the expression of major vault protein in SW620 human colon cancer cells (2008)
  • Author(s): Ikeda R, Iwashita K, Sumizawa T, Beppu S, Tabata S, Tajitsu Y, Shimamoto Y, Yoshida K, Furukawa T, Che XF, Yamaguchi T, Ushiyama M, Miyawaki A, Takeda Y, Yamamoto M, Zhao HY, Shibayama Y, Yamada K, Akiyama S
  • Journal Title: Exp. Cell Res. 314 Pages: 3017-3026
  • Peer Reviewed
• [Journal Article] Molecular basis for the induction of an angiogenesis inhibitor, thrombospondin-1, by 5-fluorouracil (2008)
  • Author(s): Zhao HY, Ooyama A, Yamamoto M, Ikeda R, Haraguchi M, Tabata S, Furukawa T, Che XF, Zhang S, Oka T, Fukushima M, Nakagawa M, Ono M, Kuwano M, Akiyama S
  • Journal Title: Cancer Res. 68 Pages: 7035-7041
  • Peer Reviewed
• [Journal Article] Down regulation of c-Myc and induction of an angiogenesis inhibitor, thrombospondin-1, by 5-FU in human colon cancer KM12C cells (2008)
  • Author(s): Zhao HY, Ooyama A, Yamamoto M, Ikeda R, Haraguchi M, Tab ata S, Furukawa T, Che XF, I washita K, Oka T, Fukushima M, Nakagawa M, Ono M, Kuwano M, Akiyama S
  • Journal Title: Cancer Lett. 270 Pages: 156-163
  • Peer Reviewed
• [Journal Article] 口腔癌治療時に汎用される院内製剤アズノール含嗽水の安定性と細菌学的検討 (2008)
  • Author(s): 牛山美奈、池田龍二、新田哲也、田實裕介、宮脇昭彦、山口辰哉、下堂薗権洋、牛ノ濱風見、松井竜太郎、杉山一正、中村典史、山田勝士
  • Journal Title: 歯科薬物療法 27 Pages: 143-150
  • NAID: 10023976819
  • Peer Reviewed
• [Presentation] チミジンホスホリラーゼ発現腫瘍での5-fluorouracil (5-FU)によるearly gr owth response factor-1 (EGR-1)発現誘導 (2009)
  • Author(s): 西澤由紀彦、池田龍二、田實裕介、俣木博徳、武田泰生、古川龍彦、牛山美奈、山口辰哉、車暁芳、山本雅達、松下茂人、秋山伸一、山田勝士
  • Organizer: 第2 6回日本薬学会九州支部大会
  • Place of Presentation: 九州大学大学院薬学研究院(福岡市)
  • Year and Date: 2009-12-12
• [Presentation] チミジンホスホリラーゼ発現腫瘍での5-fluorouracil (5-FU)によるearly growth response factor-1 (EGR-1)発現誘導 (2009)
  • Author(s): 西澤由紀彦、池田龍二、田實裕介、俣木博徳、武田泰生、古川龍彦、牛山美奈、山口辰哉、車暁芳、山本雅達、松下茂人、秋山伸一、山田勝士
  • Organizer: 第26回日本薬学会九州支部大会
  • Place of Presentation: 九州大学大学院薬学研究院(福岡市)
  • Year and Date: 2009-12-12
• [Presentation] 高浸透圧によって誘導されるmajor vault protein (MVP)の発現亢進機構の解明 (2009)
  • Author(s): 田實裕介、池田龍二、岩下健一、田畑祥、西澤由紀彦、山口辰哉、牛山美奈、山本雅達、車暁芳、古川龍彦、武田泰生、秋山伸一、山田勝士
  • Organizer: 第62回日本薬理学会西南部会
  • Place of Presentation: リジェール松山(松山市)
  • Year and Date: 2009-11-27
• [Presentation] RNA-タンパク質複合体vaultはヒト腎癌由来細胞株ACHN細胞においてhypoxia-induci ble factor-1α(HIF-1α)と結合し、そのユビキチン依存的な分解を促進する (2009)
  • Author(s): 岩下健一、池田龍二、武田泰生、住澤知之、古川龍彦、山口辰哉、秋山伸一、山田勝士
  • Organizer: 第62回日本薬理学会西南部会
  • Place of Presentation: リジェール松山(松山市)
  • Year and Date: 2009-11-27
• [Presentation] RNA-タンパク質複合体vaultはヒト腎癌由来細胞株ACHN細胞においてhypoxia-inducible factor-1α(HIF-1α)と結合し、そのユビキチン依存的な分解を促進する (2009)
  • Author(s): 岩下健一、池田龍二、武田泰生、住澤知之、古川龍彦、山口辰哉、秋山伸一、山田勝士
  • Organizer: 第62回日本薬理学会西南部会
  • Place of Presentation: リジェール松山(松山市)
  • Year and Date: 2009-11-27
• [Presentation] Gemcitabine耐性細胞でのCNT1、RRM1の発現変化 (2009)
  • Author(s): 古川龍彦、池田龍二、小松正治、秋山伸一
  • Organizer: 第68回日本癌学会学術総会
  • Place of Presentation: パシフィコ横浜(横浜市)
  • Year and Date: 2009-10-03
• [Presentation] チミジンホスホリラーゼによるNF-KBの活性化機構 (2009)
  • Author(s): 田畑祥、山本雅達、池田龍二、古川龍彦、車暁芳、新里能成、南謙太朗、向田直史、武田泰生、山田勝士、秋山伸一
  • Organizer: 第68回日本癌学会学術総会
  • Place of Presentation: パシフィコ横浜(横浜市)
  • Year and Date: 2009-10-03
• [Presentation] Gemcitabine耐性細胞でのCNT1,RRM1の発現変化 (2009)
  • Author(s): 古川龍彦、池田龍二、小松正治、秋山伸一
  • Organizer: 第68回日本癌学会学術総会
  • Place of Presentation: パシフィコ横浜(横浜市)
  • Year and Date: 2009-10-03
• [Presentation] 咽頭がん細胞KCP-4のシスプラチン耐性機序の解明 (2009)
  • Author(s): 大磯茂、池田龍二、中村和男、武田泰生、秋山伸一、山田勝士
  • Organizer: 日本薬学会第129回年会
  • Place of Presentation: 国立京都国際会館(京都市)
  • Year and Date: 2009-03-28
• [Presentation] 口腔癌治療における抗がん剤感受性試験の取り組み (2009)
  • Author(s): 牛山美奈、池田龍二、宮脇昭彦、田實裕介、西澤由紀彦、山口辰哉、中村典史、武田泰生、山田勝士
  • Organizer: 日本薬学会第129回年会
  • Place of Presentation: 国立京都国際会館(京都市)
  • Year and Date: 2009-03-28
• [Presentation] 高浸透圧によるMajor Vault Protein(MVP)の発現元進機構 (2009)
  • Author(s): 田實裕介、池田龍二、岩下建一、武田泰生、田畑祥、西澤由紀彦、牛山美奈、山口辰哉、山本雅達、車暁芳、古川龍彦、秋山伸一、山田勝士
  • Organizer: 第82回日本薬理学会年会
  • Place of Presentation: パシフィコ横浜(横浜市)
  • Year and Date: 2009-03-17
• [Presentation] 銅輸送体ATP7A・核酸輸送体CNTの関する抗癌剤耐性 (2009)
  • Author(s): 古川龍彦、池田龍二、小松正治、秋山伸一
  • Organizer: 第82回日本薬理学会年会
  • Place of Presentation: パシフィコ横浜(横浜市)
  • Year and Date: 2009-03-16
• [Presentation] 骨芽細胞分化におけるPLZFの機能的関与 (2008)
  • Author(s): 池田龍二、吉田建一、武田泰生、井ノ上逸朗、山田勝士
  • Organizer: 第2回次世代を担う若手医療薬科学シンポジウム
  • Place of Presentation: 京都大学薬学部記念講堂(京都市)
  • Year and Date: 2008-12-20
• [Presentation] チミジンホスホリラーゼ発現腫瘍細胞におけるNF-κBを介したIL-8の発現亢進機構 (2008)
  • Author(s): 田畑祥、山本雅達、池田龍二、古川龍彦、車暁芳、趙紅業、王嘉、向田直史、武田泰生、山田勝士、秋山伸一
  • Organizer: 第67回日本癌学会学術総会
  • Place of Presentation: 名古屋国際会議場(名古屋市)
  • Year and Date: 2008-10-29
• [Presentation] ヒト大腸癌における5-FUによる血管新生阻害因子TSP-1の誘導 (2008)
  • Author(s): 趙紅業、大山明雄、山本雅達、池田龍二、原口みさ子、田畑祥、古川龍彦、車暁芳、岡俊範、福島正和、小野眞弓、桑野信彦、秋山伸一
  • Organizer: 第67回日本癌学会学術総会
  • Place of Presentation: 名古屋国際会議場(名古屋市)
  • Year and Date: 2008-10-29
• [Presentation] 膵癌細胞株MIAPaCa-2由来Gemcitabine耐性細胞の耐性機構の解析 (2008)
  • Author(s): 古川龍彦、小松正治、池田龍二、秋山伸一
  • Organizer: 第67回日本癌学会学術総会
  • Place of Presentation: 名古屋国際会議場(名古屋市)
  • Year and Date: 2008-10-29
• [Presentation] survivinペプチド(89-104アミノ酸)によるATL細胞のアポトーシス誘導 (2008)
  • Author(s): 車暁芳、鄭春雷、古川龍彦、山本雅達、王嘉、池田龍二、有馬直道、秋山伸一
  • Organizer: 第67回日本癌学会学術総会
  • Place of Presentation: 名古屋国際会議場(名古屋市)
  • Year and Date: 2008-10-29
• [Presentation] 低酸素によるヒト線維芽細胞でのPGISの高発現 (2008)
  • Author(s): 王嘉、車暁芳、大山明雄、山本雅達、古川龍彦、池田龍二、鄭春雷、蓮井和久、岡俊範、秋山伸一
  • Organizer: 第67回日本癌学会学術総会
  • Place of Presentation: 名古屋国際会議場(名古屋市)
  • Year and Date: 2008-10-29
• [Presentation] チミジンホスホリラーゼ発現腫瘍細胞におけるNF-κBを介したlL-8の発現元進機構 (2008)
  • Author(s): 田畑祥、山本雅達、池田龍二、古川龍彦、車暁芳、趙紅業、王嘉、向田直史、武田泰生、山田勝士、秋山伸一
  • Organizer: 第67回日本癌学会学術総会
  • Place of Presentation: 名古屋国際会議場(名古屋市)
  • Year and Date: 2008-10-29
• [Presentation] 膵癌細胞株MIAPaCa-2由来GemGitabine耐性細胞の耐性機構の解析 (2008)
  • Author(s): 古川龍彦、小松正治、池田龍二、秋山伸一
  • Organizer: 第67回日本癌学会学術総会
  • Place of Presentation: 名古屋国際会議場(名古屋市)
  • Year and Date: 2008-10-29
• [Presentation] P53R2標的siRNAは悪性黒色腫の腫瘍増殖を抑制して抗癌剤感受性を高める (2008)
  • Author(s): 松下茂人、池田龍二、奥村浩、秋山伸一、金蔵拓郎
  • Organizer: 第67回日本癌学会学術総会
  • Place of Presentation: 名古屋国際会議場(名古屋市)
  • Year and Date: 2008-10-28
• [Presentation] 高浸透圧によるMajor Vault Protein (MVP)の発現亢進機構
  • Author(s): 田實裕介、池田龍二、岩下建一、武田泰生、田畑祥、西澤由紀彦、牛山美奈、山口辰哉、山本雅達、車暁芳、古川龍彦、秋山伸一、山田勝士
  • Organizer: 20090317
  • Place of Presentation: パシフィコ横浜(横浜市)
• [Book] Focus on Zinc Finger Protein Research(Roles of PLZF and FAZF in osteoblast differentiation) (2009)
  • Author(s): Ikeda, R., Yoshida, K., Inoue, I.