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TP53 mutation drives cancer IR-resistance via the Arf6-based pathway

Research Project

Project/Area Number 26293057
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypePartial Multi-year Fund
Section一般
Research Field General medical chemistry
Research InstitutionHokkaido University

Principal Investigator

Sabe Hisataka  北海道大学, 医学(系)研究科(研究院), 教授 (40187282)

Project Period (FY) 2014-04-01 – 2017-03-31
Project Status Completed (Fiscal Year 2016)
Budget Amount *help
¥16,120,000 (Direct Cost: ¥12,400,000、Indirect Cost: ¥3,720,000)
Fiscal Year 2016: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000)
Fiscal Year 2015: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000)
Fiscal Year 2014: ¥6,760,000 (Direct Cost: ¥5,200,000、Indirect Cost: ¥1,560,000)
Keywords放射線抵抗性 / Arf6 / TP53 / AMAP1 / β1 integrin / メバロン酸代謝活性 / ミトコンドリア / 酸化的リン酸化 / 変異p53 / 癌放射線抵抗性 / Arf6経路 / 代謝 / 微小管 / 細胞内器官配置 / 活性酸素 / Arf6 / 細胞内配置
Outline of Final Research Achievements

Ionizing radiation (IR) is amongest a promissing method of the cancer therapeutics. We have shown previous that the small-GTPase Arf6 and its downstream signaling factors are frequently overexpressed in different cancers and execute a cancer mesenchymal program, including invasion and metastasis. We have furthermore identified that this pathway is a core to promote IR-resistance of cancer cells. Here, we show a precise mechanism by which the Arf6-based pathway contributes to the cancer IR-resistance, and identified a critical gene mutation therein involved.

Report

(4 results)
  • 2016 Annual Research Report   Final Research Report ( PDF )
  • 2015 Annual Research Report
  • 2014 Annual Research Report
  • Research Products

    (31 results)

All 2016 2015 2014 Other

All Journal Article (8 results) (of which Int'l Joint Research: 1 results,  Peer Reviewed: 8 results,  Open Access: 7 results,  Acknowledgement Compliant: 4 results) Presentation (18 results) (of which Int'l Joint Research: 2 results,  Invited: 4 results) Book (1 results) Remarks (3 results) Patent(Industrial Property Rights) (1 results)

  • [Journal Article] Arf6 and its ZEB1-EPB41L5 mesenchymal axis are required for both mesenchymal- and amoeboid-type invasion of cancer cells.2016

    • Author(s)
      Handa H, Hashimoto A, Hashimoto S, Sabe, H.
    • Journal Title

      Small GTPases

      Volume: - Issue: 5 Pages: 28-28

    • DOI

      10.1080/21541248.2016.1249043

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed
  • [Journal Article] High expression of the mesenchymal protein EPB41L5 correlates with poor prognosis of head and neck squamous cell carcinoma.2016

    • Author(s)
      Otsuka Y, Sato H, Oikawa T, Onodera Y, Nam JM, Hashimoto A, Fukunaga K, Hatanaka KC, Hatanaka Y, Matsuno Y, Fukuda S, Sabe H.
    • Journal Title

      Cell Comm. Signal.

      Volume: 14 Issue: 1 Pages: 28-28

    • DOI

      10.1186/s12964-016-0151-0

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Acquired platinum resistance involves epithelial-to-mesenchymal transition through ubiquitin ligase FBXO32 dysregulation2016

    • Author(s)
      Tanaka N, Kosaka T, Miyazaki Y, Mikami S, Niwa N, Otsuka Y, Minamishima YA, Mizuno R, Kikuchi E, Miyajima A, Sabe H, Okada Y, Uhlen P, Suematsu M, Oya M
    • Journal Title

      JCI insight

      Volume: 1 Issue: 18

    • DOI

      10.1172/jci.insight.83654

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] ZEB1 induces EPB41L5 in the cancer mesenchymal program that drives ARF6-based invasion, metastasis, and drug resistance.2016

    • Author(s)
      Hashimoto A, Hashimoto S, Sugino H, Yoshikawa A, Onodera Y, Handa H, Oikawa T, Sabe H.
    • Journal Title

      Oncogenesis.

      Volume: 5 Issue: 9 Pages: e259-e259

    • DOI

      10.1038/oncsis.2016.60

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] The Rho guanine nucleotide exchange factor ARHGEF5 promotes tumor malignancy via epithelial-mesenchymal transition2016

    • Author(s)
      Komiya Y, Onodera Y, Kuroiwa M, Nomimura S, Kubo Y, Nam JM, Kajiwara K, Nada S, Oneyama C, Sabe H, Okada M.
    • Journal Title

      Oncogenesis

      Volume: 5 Issue: 9 Pages: e258-e258

    • DOI

      10.1038/oncsis.2016.59

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Journal Article] P53- and mevalonate pathway-driven malignancies require Arf6 for metastasis and drug resistance.2016

    • Author(s)
      Hashimoto, A., Oikawa, T., Hashimoto, S., Sugino, H., Yoshikawa, A., Otsuka, Y., Handa, H., Onodera, Y., Nam, J.M., Oneyama, C., Okada, M., Fukuda M. and Sabe, H.
    • Journal Title

      J Cell Biol.

      Volume: 213 Issue: 1 Pages: 81-95

    • DOI

      10.1083/jcb.201510002

    • NAID

      120005763128

    • Related Report
      2016 Annual Research Report 2015 Annual Research Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Journal Article] Lysophosphatidic acid activates Arf6 to promote the mesenchymal malignancy of renal cancer.2016

    • Author(s)
      Hashimoto, S,. Mikami, S., Sugino, H., Yoshikawa, A., Hashimoto, A., Onodera, Y., Furukawa, S., Handa, H., Oikawa, T., Okada, Y., Oya, M. and Sabe, H.
    • Journal Title

      Nat. Commun.

      Volume: 7 Issue: 1 Pages: 10656-10656

    • DOI

      10.1038/ncomms10656

    • NAID

      120005743066

    • Related Report
      2016 Annual Research Report 2015 Annual Research Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Journal Article] AMAP1 as a negative-feedback regulator of nuclear factor-κB under inflammatory conditions.2014

    • Author(s)
      Tien, D.N., Kishihata, M., Yoshikawa, A., Hashimoto, A., Sabe, H., Nishi, E., Kamei, K., Arai, H., Kita, T., Kimura, T., Yokode, M. and Ashida, N.
    • Journal Title

      Sci Rep.

      Volume: 4 Issue: 1 Pages: 5094-5094

    • DOI

      10.1038/srep05094

    • Related Report
      2014 Annual Research Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Presentation] がん細胞における小胞輸送経路を介したミトコンドリア分布制御と活性酸素お よび放射線への耐性2016

    • Author(s)
      Yasuhito Onodera, Jin-Min Nam, Hiroki Shirato, Hisataka Sabe
    • Organizer
      日本放射線影響学会 第59回大会
    • Place of Presentation
      JMSアステールプラザ(広島市)
    • Year and Date
      2016-10-26
    • Related Report
      2016 Annual Research Report
  • [Presentation] p53 antagonizes EZH2 function to maintain epithelial integrity2016

    • Author(s)
      Tsukasa Oikawa, Yutaro Otsuka, Yasuhito Onodera, Haruka Handa, Ari Hashimoto, Shigeru Hashimoto, Yutaka Suzuki, Hisataka Sabe
    • Organizer
      第75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
      2016-10-06
    • Related Report
      2016 Annual Research Report
  • [Presentation] Tumor responsiveness to mevalonate pathway inhibitors require overexpression of the Arf6 pathway2016

    • Author(s)
      Ari Hashimoto, Shigeru Hashimoto, Tsukasa Oikawa, Yutaro Otsuka, Haruka Handa, Yasuhito Onodera, Hisataka Sabe
    • Organizer
      第89回日本生化学会
    • Place of Presentation
      仙台国際センター(仙台市)
    • Year and Date
      2016-09-25
    • Related Report
      2016 Annual Research Report
  • [Presentation] 癌的代謝亢進によるミトコンドリア空間配置:転移性癌の治療抵抗性について2016

    • Author(s)
      Hisataka Sabe
    • Organizer
      第11回Basic Research Urology Seminar(BURS)
    • Place of Presentation
      ANAクラウンプラザホテル千歳(千歳市)
    • Year and Date
      2016-08-27
    • Related Report
      2016 Annual Research Report
    • Invited
  • [Presentation] Malignant phenotype mediated by metabolism, transport and compartmentalization2016

    • Author(s)
      Yasuhito Onodera, Mina Bissell, Hisataka Sabe
    • Organizer
      第68回日本細胞生物学会大会
    • Place of Presentation
      京都テルサ(京都市)
    • Year and Date
      2016-06-15
    • Related Report
      2016 Annual Research Report
  • [Presentation] Arf6 is a core driver of mesenchymal invasion and metastasis, and therapeutic resistance of different types of cancers under RTK and GPCR signaling2016

    • Author(s)
      Hisataka Sabe, Shigeru Hashimoto, Ari Hashimoto, Yutaro Otsuka, Haruka Handa, Tsukasa Oikawa, and Yasuhito Onodera
    • Organizer
      第68回日本細胞生物学会大会
    • Place of Presentation
      京都テルサ(京都市)
    • Year and Date
      2016-06-15
    • Related Report
      2016 Annual Research Report
    • Invited
  • [Presentation] Arf6-AMAP1 pathway drives mesenchymal metastasis and drug resistance of cancers under RTK and GPCR signaling2016

    • Author(s)
      Hisataka Sabe
    • Organizer
      OOTR第12回年次学会
    • Place of Presentation
      ウエスティン都ホテル京都(京都府・京都市)
    • Year and Date
      2016-03-03
    • Related Report
      2015 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] p53 warrants epithelial gene expressions through epigenetic regulation2015

    • Author(s)
      Tsukasa Oikawa, Yasuhito Onodera, Yutaro Otsuka, Haruka Handa, Ari Hashimoto, Shigeru Hashimoto, Yutaka Suzuki and Hisataka Sabe
    • Organizer
      BMB2015(第38回日本分子生物学会年会、第88回日本生化学会大会 合同大会)
    • Place of Presentation
      神戸ポートアイランド(兵庫県・神戸市)
    • Year and Date
      2015-12-01
    • Related Report
      2015 Annual Research Report
  • [Presentation] Arf6-AMAP1 pathway confers radioresistance via regulation of ROS in breast cancer2015

    • Author(s)
      Yasuhito Onodera, Jin-Min Nam, Tsukasa Oikawa, Hiroki Shirato, Hisataka Sabe
    • Organizer
      第74回日本癌学会学術総会
    • Place of Presentation
      名古屋国際会議場(愛知県・名古屋市)
    • Year and Date
      2015-10-06
    • Related Report
      2015 Annual Research Report
  • [Presentation] Grb2 promotes cancer invasive activities via EGF-induced GEP100-Arf6 pathway2015

    • Author(s)
      Toshi Menju, Naoto Imamura, Shinya Neri, Hiroyuki Cho, Takao Nakanishi, Kei Shikuma, Terumasa Sowa, Makoto Sonobe, Hisataka Sabe, Stephan M Feller, Hiroshi Date
    • Organizer
      第18回欧州癌学会、第40回欧州癌治療学会 共催
    • Place of Presentation
      Messe Wien Exhibition & Congress Center(ウィーン・オーストリア)
    • Year and Date
      2015-09-25
    • Related Report
      2015 Annual Research Report
    • Int'l Joint Research
  • [Presentation] ZEB1-EPB4.1L5 axis drives mesenchymal-type invasion and metastasis of primary breast cancers2015

    • Author(s)
      Ari Hashimoto, Shigeru Hashimoto, Hirokazu Sugino, Ayumu Yoshikawa, Haruka Handa, Yutaro Otsuka, Jin-Min Nam, Yasuhito Onodera, Tsukasa Oikawa and Hisataka Sabe
    • Organizer
      第67回日本細胞生物学会大会
    • Place of Presentation
      タワーホール船堀(東京都・江戸川区)
    • Year and Date
      2015-06-30
    • Related Report
      2015 Annual Research Report
  • [Presentation] Different genome statuses in breast cancer and renal cancer generate the Arf6-based mesenchymal machinery critical for metastasis and poor survival2014

    • Author(s)
      Hisataka Sabe, Ari Hashimoto, Shigeru Hashimoto, Hirokazu Sugino, Ayumu Yoshikawa, Haruka Handa, Yutaro Otsuka, Tsukasa Oikawa, Shuji Mikami, Mototsugu Oya
    • Organizer
      The 4th Global Cancer Genomics Consortium Symposium
    • Place of Presentation
      芝蘭会館(京都市)
    • Year and Date
      2014-11-14 – 2014-11-15
    • Related Report
      2014 Annual Research Report
    • Invited
  • [Presentation] p53 recalls epithelial memory in mammary cancer cells with mesenchymal phenotypes2014

    • Author(s)
      Tsukasa Oikawa, Yasuhito Onodera, Ari Hashimoto, Shigeru Hashimoto, and Hisataka Sabe
    • Organizer
      第73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
      2014-09-25 – 2014-09-27
    • Related Report
      2014 Annual Research Report
  • [Presentation] Analysis of molecular mechanism involved in invasiveness of2014

    • Author(s)
      Jin-Min Nam, Yasuhito Onodera, Hisataka Sabe, Hiroki Shirato
    • Organizer
      第73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
      2014-09-25 – 2014-09-27
    • Related Report
      2014 Annual Research Report
  • [Presentation] EZH2 generates Arf6-based mesenchymal invasion machinery2014

    • Author(s)
      shigeru Hashimoto, Hirokazu Sugino, Ari Hashimoto, Ayumu
    • Organizer
      第73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
      2014-09-25 – 2014-09-27
    • Related Report
      2014 Annual Research Report
  • [Presentation] TP53 alterations generate Arf6-based mesenchymal invasion pathway that is activated by RTKs and TGFβ1 in breast cancer2014

    • Author(s)
      Ari Hashimoto, Shigeru Hashimoto, Hirokazu Sugino, Ayumu Yoshikawa, Tsukasa Oikawa, Yasuhito Onodera, Haruka Handa, Yutaro Otsuka, Kosuke Iwami, Hiroki Sato, Chitose Oneyama, Masato Okada, Satoshi Fukuda, Mitsunori Fukuda, and Hisataka Sabe
    • Organizer
      第73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
      2014-09-25 – 2014-09-27
    • Related Report
      2014 Annual Research Report
  • [Presentation] Robust redox homeostasis mediated by Arf6-AMAP1 pathway confers resistance to ionizing radiation in breast cancer2014

    • Author(s)
      Yasuhito Onodera, Jin-Min Nam, Tsukasa Oikawa, Hiroki Shirato and Hisataka Sabe
    • Organizer
      第73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
      2014-09-25 – 2014-09-27
    • Related Report
      2014 Annual Research Report
  • [Presentation] EZH2 overexpression generates Arf6-based mesenchymal invasion machinery that is activated by LPA and central to poor prognosis of renal cancer2014

    • Author(s)
      Shigeru Hashimoto, Hirokazu Sugino, Ari Hashimoto, Ayumu Yoshikawa, Tsukasa Oikawa, Haruka Handa, Mototsugu Oya, Shuji Mikami, and Hisataka Sabe
    • Organizer
      Mechanisms & Models of Cancer
    • Place of Presentation
      Cold Spring Harbor Laboratory(USA)
    • Year and Date
      2014-08-12 – 2014-08-16
    • Related Report
      2014 Annual Research Report
  • [Book] ArfGAPs: not only for the termination.2014

    • Author(s)
      Shigeru Hashimoto, Ari Hashimoto, Hirokazu Sugino, Ayumu Yoshikawa, Haruka Handa, Masanao Yoshino, Yutaro Otsuka, and Hisataka Sabe.
    • Total Pages
      22
    • Publisher
      Springer
    • Related Report
      2014 Annual Research Report
  • [Remarks] 北海道大学大学院医学研究院 生化学講座分子生物学教室ホームページ

    • URL

      http://g21001.med.hokudai.ac.jp/

    • Related Report
      2016 Annual Research Report
  • [Remarks] 北海道大学大学院医学研究科 生化学講座分子生物学分野ホームページ

    • URL

      http://www.hucc.hokudai.ac.jp/~g21001/

    • Related Report
      2015 Annual Research Report
  • [Remarks] 北海道大学大学院医学研究科生化学講座分子生物学分野ホームページ

    • URL

      http://www.hucc.hokudai.ac.jp/~g21001/

    • Related Report
      2014 Annual Research Report
  • [Patent(Industrial Property Rights)] 腎癌の再発リスクの予測に用いるための診断薬及びキット、並びに予測方法2015

    • Inventor(s)
      佐邊壽孝、平野聡、古川聖太郎
    • Industrial Property Rights Holder
      佐邊壽孝、平野聡、古川聖太郎
    • Industrial Property Rights Type
      特許
    • Filing Date
      2015-12-17
    • Related Report
      2015 Annual Research Report

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Published: 2014-04-04   Modified: 2018-03-22  

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