Generation of malignant tumor model by heme synthesis failure using mice with Abcb10 deficient

• Project/Area Number: 23701037
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Carcinogenesis
• Research Institution: Kagoshima University
• Principal Investigator: YAMAMOTO Masatatsu 鹿児島大学, 医歯(薬)学総合研究科, 助教 (40404537)
• Project Period (FY): 2011 – 2012
• Project Status: Completed (Fiscal Year 2013)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2012: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2011: ¥2,730,000 (Direct Cost: ¥2,100,000、Indirect Cost: ¥630,000)
• Keywords: 腫瘍学発ガン

Research Abstract

To investigate how Abcb10 deficiency affect to the accumulation of PPIX and malignant potential of tumor cells, we tried to generate allogeneic tumor transplantation-metastasis models from DEN exposed Abcb10-/-mice. We picked up several cells from liver tumors of Abcb10-/-mice, however could not obtain any tumor cells that acquired spontaneous metastatic potential.
We explored in detail the relevance of the physiological role of Abcb10 to the tumorigenesis. Abcb10 deficiency resulted in a defect of heme biosynthesis but did not affect to the stability of Fech. Electron microscopy images of Abcb10-/- hematopoietic cells showed marked iron deposits at the mitochondria. Abcb10F/-; Mx1-Cre mice, with the specific deletion of Abcb10 in hematopoietic cells, showed PPIX accumulation and maturation arrest in reticulocytes.These results suggest a critical role for Abcb10 in heme biosynthesis and provide new insights into the pathogenesis of erythropoietic protoporphyria and sideroblastic anemia.

Research Products

• [Journal Article] Design and synthesis of prostate cancer antigen-1 (PCA-1/ALKBH3) inhibitors as anti-prostate cancer drugs (2014)
  • Author(s): Nakao S, Mabuchi M, Shimizu T, Itoh Y, Takeuchi Y, Ueda M, Mizuno H, Shigi N, Ohshio I, Jinguji K, Ueda Y, Yamamoto M, Furukawa T, Aoki S, Tsujikawa K, Tanaka A.
  • Journal Title: Bioorg Med Chem Lett. Volume: Vol.24,No.3 Pages: 1071-1074
  • Peer Reviewed
• [Journal Article] Abcb10 role in heme biosynthesis in vivo : Abcb10 knockout in mice causes anemia with protoporphyrin IX and iron accumulation (2014)
  • Author(s): Yamamoto M, Arimura H, Fukushige T, Minami K, Nishizawa Y, Tanimoto A, Kanekura T, Nakagawa M, Akiyama S, Furukawa T
  • Journal Title: Mol Cell Biol. Volume: Vol.34,No.6 Pages: 1077-1084
  • Peer Reviewed
• [Journal Article] Abcb10 role in heme biosynthesis in vivo: Abcb10 knockout in mice causes anemia with protoporphyrin IX and iron accumulation. (2014)
  • Author(s): Yamamoto M, Arimura H, Fukushige T, Minami K, Nishizawa Y, Tanimoto A, Kanekura T, Nakagawa M, Akiyama S, Furukawa T
  • Journal Title: Mol Cell Biol. Volume: 6 Issue: 6 Pages: 1077-84
  • DOI: 10.1128/mcb.00865-13
  • Peer Reviewed
• [Journal Article] Design and synthesis of prostate cancer antigen-1 (PCA-1/ALKBH3) inhibitors as anti-prostate cancer drugs. (2014)
  • Author(s): S. Nakao, M. Mabuchi, T.Shimizu, Y. Itoh, Y. Takeuchi, M. Ueda, H. Mizuno, N. Shigi, I. Ohshio, K. Jinguji, Y. Ueda, M. Yamamoto, T. Furukawa, S. Aoki, K. Tsujikawa, A. Tanaka
  • Journal Title: Bioorganic & Medicinal Chemistry Letters Volume: 24 Issue: 4 Pages: 1071-1074
  • DOI: 10.1016/j.bmcl.2014.01.008
  • Peer Reviewed
• [Journal Article] Reduction of MLH1 and PMS2 confers temozolomide resistance and is associated with recurrence of glioblastoma. (2014)
  • Author(s): Shinsato Y, Furukawa T, Yunoue S, Yonezawa H, Minami K, Nishizawa Y, Ikeda R, Kawahara K, Yamamoto M, Hirano H, Tokimura H, Arita K
  • Journal Title: Oncotarget. Volume: 12 Pages: 2261-70
  • Peer Reviewed
• [Journal Article] Molecular basis for the expression of major vault protein induced by hyperosmotic stress in SW620 human colon cancer cells. (2014)
  • Author(s): Tajitsu Y, Ikeda R, Nishizawa Y, Mataki H, Che XF, Sumizawa T, Nitta M, Yamaguchi T, Yamamoto M, Tabata S, Akiyama S, Yamada K, Furukawa T, Takeda Y
  • Journal Title: Int J Mol Med Volume: 3 Issue: 3 Pages: 703-8
  • DOI: 10.3892/ijmm.2013.1428
  • Peer Reviewed
• [Journal Article] Molecular basis for the regulation of hypoxia-inducible factor-1α levels by 2-deoxy-D-ribose. (2014)
  • Author(s): Ikeda R, Tabata S, Tajitsu Y, Nishizawa Y, Minami K, Furukawa T, Yamamoto M, Shinsato Y, Akiyama S, Yamada K, Takeda Y
  • Journal Title: Oncol Rep Volume: 3 Issue: 3 Pages: 1444-8
  • DOI: 10.3892/or.2013.2572
  • Peer Reviewed
• [Journal Article] Reduction of MLH1 and PMS2 confers temozolomide resistance and is associated with recurrence of glioblastoma (2013)
  • Author(s): Shinsato Y, Furukawa T, Yunoue S, Yonezawa H, Minami K, Nishizawa Y, Ikeda R, Kawahara K, Yamamoto M, Hirano H, Tokimura H, Arita K
  • Journal Title: Oncotarget. Volume: Vol.4,No.12 Pages: 2261-2270
  • Peer Reviewed
• [Journal Article] Influence of gefitinib and erlotinib on apoptosis and c-MYC expression in H23 lung cancer cells (2013)
  • Author(s): Suenaga M, Yamamoto M, Tabata S, Itakura S, Miyata M, Hamasaki S, Furukawa T
  • Journal Title: Anticancer Res Volume: Vol.33,No.4 Pages: 1547-1554
  • Peer Reviewed
• [Journal Article] VEGF expression is augmented by hypoxia-induced PGIS in human fibroblasts (2013)
  • Author(s): Wang J, Ikeda R, Che XF, Ooyama A, Yamamoto M, Furukawa T, Hasui K, Zheng CL, Tajitsu Y, Oka T, Tabata S, Nishizawa Y, Eizuru Y, Akiyama S
  • Journal Title: Int J Oncol. Volume: Vol.43,No.3 Pages: 746-753
  • Peer Reviewed
• [Journal Article] Molecular basis for the regulation of hypoxia-inducible factor-1α levels by 2-deoxy-D-ribose (2013)
  • Author(s): Ikeda R, Tabata S, Tajitsu Y, Nishizawa Y, Minami K, Furukawa T, Yamamoto M, Shinsato Y, Akiyama S, Yamada K, Takeda Y
  • Journal Title: Oncol Rep. Volume: Vol.30,No.3 Pages: 1444-1448
  • Peer Reviewed
• [Journal Article] Molecular basis for the expression of major vault protein induced by hyperosmotic stress in SW620 human colon cancer cells (2013)
  • Author(s): Tajitsu Y, Ikeda R, Nishizawa Y, Mataki H, Che XF, Sumizawa T, Nitta M, Yamaguchi T, Yamamoto M, Tabata S, Akiyama S, Yamada K, Furukawa T, Takeda Y
  • Journal Title: Int J Mol Med. Volume: Vol.32,No.3 Pages: 703-708
  • Peer Reviewed
• [Journal Article] Influence of gefitinib and erlotinib on apoptosis and c-MYC expression in H23 lung cancer cells. (2013)
  • Author(s): Suenaga M, Yamamoto M, Tabata S, Itakura S, Miyata M, Hamasaki S, Furukawa T
  • Journal Title: Anticancer Res Volume: 4 Pages: 1547-54
• [Journal Article] Thymidine phosphorylase enhances reactive oxygen species generation and interleukin-8 expression in human cancer cells (2012)
  • Author(s): Tabata S1, Ikeda R, Yamamoto M, Furukawa T, Kuramoto T, Takeda Y, Yamada K, Haraguchi M, Nishioka Y, Sone S, Akiyama S
  • Journal Title: Oncol Rep. Volume: Vol.3 Pages: 895-902
  • Peer Reviewed
• [Presentation] Abcb10 knockout mice causes anemia with protoporphyrin IX and iron accumulation : Abcb10 is essential for heme biosynthesisin vivo (2014)
  • Author(s): 山本雅達
  • Organizer: 生体制御・創薬研究ワークショップ
  • Place of Presentation: 鹿児島
• [Presentation] KB3-1細胞における5-aza-2-deoxycytidine (5-AZ)による 5-fluorouracil (5-FU)の抗腫瘍効果増強作用 (2014)
  • Author(s): 西澤由紀彦、池田龍二、田實裕介、河原康一、山本雅達、新里能成、南謙太郎、古川龍彦、武田泰生
  • Organizer: 日本薬理学会本会
  • Place of Presentation: 仙台
• [Presentation] Abcb10 knockout mice causes anemia with protoporphyrin IX and iron accumulation: Abcb10 is essential for heme biosynthesis in vivo. (2014)
  • Author(s): 山本雅達
  • Organizer: 生体制御・創薬研究ワークショップ
  • Place of Presentation: 鹿児島
• [Presentation] Gemcitabine耐性膵癌細胞MGEM6で増加した RRM1のノックダウンはgemcitabineの細胞内蓄積量を増加させる (2013)
  • Author(s): 南謙太朗、山本雅達、新里能成、河原康一、小松政治、池田龍二、西澤由紀彦、田畑祥、秋山伸一、山田勝士、古川龍彦、武田泰生
  • Organizer: 日本薬理学会西南部会
  • Place of Presentation: 福岡
• [Presentation] Abcb10はHeme合成に必須であって、その欠損マウスはProtoporphyrin IXと鉄の高蓄積と血球分化不全を示す (2013)
  • Author(s): 山本雅達
  • Organizer: 第8回トランスポーター研究会
  • Place of Presentation: 熊本
• [Presentation] Abcb10はHeme合成に必須であって、その欠損マウスはProtoporphyrin IXと鉄 の高蓄積と血球分化不全を示す (2013)
  • Author(s): 山本 雅達、有村 博史、福重 智子、河原 康一、中川 昌之、金蔵 拓郎、古川 龍彦
  • Organizer: 第８回トランスポーター研究会年会
  • Place of Presentation: 熊本
  • Invited
• [Presentation] シンポジウム2S13生体遷移金属のパラダイムシフト : 生体内シグナル分子としての機能『Abcb10はHeme合成に必須であって、その欠損マウスはヒトErythropoietic protoporphyriaと類似の病態を示す』 (2012)
  • Author(s): 山本雅達
  • Organizer: 第85回日本生化学会大会
  • Place of Presentation: 福岡
• [Presentation] ヒト癌細胞の生存におけるチミジン異化作用の役割 (2012)
  • Author(s): 田畑祥,池田龍二,山本雅達,古川龍彦,倉本卓哉,後東久嗣,埴淵昌毅,西岡安彦,曽根三郎,秋山伸一
  • Organizer: 第71回日本癌学会学術総会
  • Place of Presentation: 札幌
• [Presentation] ヒト癌細胞の ROS産生および生存におけるチミジン異化作用の役割 (2012)
  • Author(s): 田畑祥,池田龍二,山本雅達,古川龍彦,倉本卓哉,後東久嗣,埴淵昌毅,西岡安彦,曽根三郎,秋山伸一
  • Organizer: 第16回日本がん分子標的治療学会学術集会
  • Place of Presentation: 北九州
• [Presentation] Abcb10, the gene knockout mice exhibit similar to human Erythropoietic protoporphyria, is essential for Heme synthesis (2012)
  • Author(s): 山本雅達、有村博史、福重智子、中川昌之、金蔵拓郎、古川龍彦
  • Organizer: 第7回トランスポーター研究会
  • Place of Presentation: 京都
• [Presentation] CNT1とRRM1の発現変化がGemcitabine耐性膵癌細の耐性に関与している (2012)
  • Author(s): 古川龍彦、南謙太朗、西澤由紀彦、池田龍二、山本雅達、武田泰生
  • Organizer: 第85回日本薬理学会年会
  • Place of Presentation: 京都
• [Presentation] Abcb10はHeme合成に必須であって、その欠損マウスはヒトErythropoietic protoporphyriaと類似の病態を示す (2012)
  • Author(s): 山本雅達
  • Organizer: 第85回日本生化学会大会
  • Place of Presentation: 福岡
  • Invited
• [Presentation] Abcb10はHeme合成に必須であって、その欠損マウスはヒトErythropoietic protoporphyriaと類似の病態を示す (2011)
  • Author(s): 山本雅達、有村博史、福重智子、中川昌之、金蔵拓郎、古川龍彦
  • Organizer: 第34回日本分子生物学会年会
  • Place of Presentation: 横浜
• [Presentation] 癌細胞での 5-FU依存的 early growthresponse protein-1およびthrombospondin-1発現亢進におけるthymidinephosphorylaseの役割 (2011)
  • Author(s): 西澤由紀彦、池田龍二、松下茂人、田畑祥、山本雅達、南謙太郎、山口辰哉、秋山伸一、古川龍彦
  • Organizer: 第70回日本癌学会学術総会
  • Place of Presentation: 名古屋
• [Presentation] Gemcitabine耐性膵臓癌細胞のCNT1とRRM1の耐性機構への関与 (2011)
  • Author(s): 南謙太朗、古川龍彦、山本雅達、西澤由紀彦、田畑祥、池田龍二、小松正治、秋山伸一
  • Organizer: 第70回日本癌学会学術総会
  • Place of Presentation: 名古屋
• [Presentation] Abcb10はHeme合成に必須であって、その欠損マウスはヒトErythropoietic protoporphyriaと類似の病態を示す。 (2011)
  • Author(s): 山本 雅達，有村 博史，福重 智3，中川 昌之，金蔵 拓郎，古川 龍彦
  • Organizer: 第34回日本分子生物学会年会
  • Place of Presentation: 横浜
• [Remarks]
  • URL: http://www.kufm.kagoshima-u.ac.jp/~moloncl2/member.html