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

• Project/Area Number: 26293057
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Partial Multi-year Fund
• Section: 一般
• Research Field: General medical chemistry
• Research Institution: Hokkaido 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: ¥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.

Research Products

• [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: － Pages: 28-28
  • DOI: 10.1080/21541248.2016.1249043
  • 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 Pages: 28-28
  • DOI: 10.1186/s12964-016-0151-0
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Acquired platinum resistance involves epithelial to mesenchymal transition through ubiquitin ligase FBXO32 dysregulation. (2016)
  • 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: Journal of Clinical Investigation Insight. Volume: 1
  • DOI: 10.1172/jci.insight.83654
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [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
  • DOI: 10.1038/oncsis.2016.60
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] The Rho guanine nucleotide exchange factor ARHGEF5 promotes tumor malignancy via epithelial-mesenchymal transition. (2016)
  • 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
  • DOI: 10.1038/oncsis.2016.59
  • 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 Pages: 81-95
  • DOI: 10.1083/jcb.201510002
  • NAID: 120005763128
  • 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 Pages: 10656-10656
  • DOI: 10.1038/ncomms10656
  • NAID: 120005743066
  • 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 Pages: 5094-5094
  • DOI: 10.1038/srep05094
  • 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
• [Presentation] p53 antagonizes EZH2 function to maintain epithelial integrity (2016)
  • 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
• [Presentation] Tumor responsiveness to mevalonate pathway inhibitors require overexpression of the Arf6 pathway (2016)
  • 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
• [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
  • Invited
• [Presentation] Malignant phenotype mediated by metabolism, transport and compartmentalization (2016)
  • 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
• [Presentation] Arf6 is a core driver of mesenchymal invasion and metastasis, and therapeutic resistance of different types of cancers under RTK and GPCR signaling (2016)
  • 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
  • Invited
• [Presentation] Arf6-AMAP1 pathway drives mesenchymal metastasis and drug resistance of cancers under RTK and GPCR signaling (2016)
  • 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
  • Int'l Joint Research / Invited
• [Presentation] p53 warrants epithelial gene expressions through epigenetic regulation (2015)
  • 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
• [Presentation] Arf6-AMAP1 pathway confers radioresistance via regulation of ROS in breast cancer (2015)
  • 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
• [Presentation] Grb2 promotes cancer invasive activities via EGF-induced GEP100-Arf6 pathway (2015)
  • 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
  • Int'l Joint Research
• [Presentation] ZEB1-EPB4.1L5 axis drives mesenchymal-type invasion and metastasis of primary breast cancers (2015)
  • 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
• [Presentation] Different genome statuses in breast cancer and renal cancer generate the Arf6-based mesenchymal machinery critical for metastasis and poor survival (2014)
  • 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
  • Invited
• [Presentation] p53 recalls epithelial memory in mammary cancer cells with mesenchymal phenotypes (2014)
  • 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
• [Presentation] Analysis of molecular mechanism involved in invasiveness of (2014)
  • 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
• [Presentation] EZH2 generates Arf6-based mesenchymal invasion machinery (2014)
  • 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
• [Presentation] TP53 alterations generate Arf6-based mesenchymal invasion pathway that is activated by RTKs and TGFβ1 in breast cancer (2014)
  • 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
• [Presentation] Robust redox homeostasis mediated by Arf6-AMAP1 pathway confers resistance to ionizing radiation in breast cancer (2014)
  • 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
• [Presentation] EZH2 overexpression generates Arf6-based mesenchymal invasion machinery that is activated by LPA and central to poor prognosis of renal cancer (2014)
  • 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
• [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
• [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/
• [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/
• [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/
• [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