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Mechanisms of colon cancer malignancy regulation by two endogenous prostanoid receptors

Research Project

Project/Area Number 25460091
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Research Field Pharmacology in pharmacy
Research InstitutionChiba University

Principal Investigator

FUJINO Hiromichi  千葉大学, 薬学研究科(研究院), 准教授 (40401004)

Co-Investigator(Renkei-kenkyūsha) MURAYAMA Toshihiko  千葉大学, 大学院薬学研究院, 教授 (90174317)
Project Period (FY) 2013-04-01 – 2016-03-31
Project Status Completed (Fiscal Year 2015)
Budget Amount *help
¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000)
Fiscal Year 2015: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Fiscal Year 2014: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2013: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
KeywordsGタンパク質共役型受容体 / プロスタノイド / 細胞内情報伝達系 / バイアスリガンド / PGD2 / PGE2 / DP受容体 / EP2受容体 / 結腸癌 / 1000ゲノムプロジェクト / 受容体アミノ酸変異 / β-カテニン / 結腸癌細胞 / LS174T細胞 / DAF/CD55 / DPアンタゴニスト
Outline of Final Research Achievements

Prostaglandin D2 (PGD2) and prostaglandin E2 (PGE2) are known as positional-isomers so that they are known to cross-talk to the other receptors besides its own cognate receptors. However, the physiological roles and/or significances of the cross-talks have been remained unclear. In this study, we have elucidated that PGD2 or PGE2 acts to DP receptors or EP2 receptors not as a partial agonist but as a biased ligand followed by activating a biased signaling pathway, respectively. It is widely reported that PGD2 has a role on anti-cancer activity whereas PGE2 has a pro-cancer activity. The findings about the biased activity evoked by endogenous prostanoids as biased agonists are very significant that may answer the reasons why both prostanoids show the opposite functions in the body. We believe that our study will provide innovated ideas and/or approaches in the field of understanding physiological functions of the G protein-coupled receptors including prostanoid receptors.

Report

(4 results)
  • 2015 Annual Research Report   Final Research Report ( PDF )
  • 2014 Research-status Report
  • 2013 Research-status Report
  • Research Products

    (38 results)

All 2016 2015 2014 2013 Other

All Int'l Joint Research (1 results) Journal Article (10 results) (of which Int'l Joint Research: 2 results,  Peer Reviewed: 10 results,  Acknowledgement Compliant: 3 results,  Open Access: 2 results) Presentation (23 results) (of which Invited: 1 results) Remarks (3 results) Patent(Industrial Property Rights) (1 results)

  • [Int'l Joint Research] アリゾナ大学(米国)

    • Related Report
      2015 Annual Research Report
  • [Journal Article] The Roles of EP4 Prostanoid Receptors in Cancer Malignancy Signaling2016

    • Author(s)
      Fujino H.
    • Journal Title

      Biological and Pharmaceutical Bulletin

      Volume: 39 Issue: 2 Pages: 149-155

    • DOI

      10.1248/bpb.b15-00840

    • NAID

      130005122367

    • ISSN
      0918-6158, 1347-5215
    • Related Report
      2015 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Prostaglandin E2-stimulated prostanoid EP4 receptors induce prolonged de novo prostaglandin E2 synthesis through biphasic phosphorylation of extracellular signal-regulated kinases mediated by activation of protein kinase A in HCA-7 human colon cancer cells.2015

    • Author(s)
      Fujino H, Seira N, Kurata N, Araki Y, Nakamura H, Regan JW, Murayama T.
    • Journal Title

      Eur J Pharmacol

      Volume: 768 Pages: 149-159

    • DOI

      10.1016/j.ejphar.2015.10.044

    • Related Report
      2015 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] L-cysteine/d,L-homocysteine-regulated ileum motility via system L and B°,+ transporter: Modification by inhibitors of hydrogen sulfide synthesis and dietary treatments.2015

    • Author(s)
      Yamane S, Nomura R, Yanagihara M, Nakamura H, Fujino H, Matsumoto K, Horie S, Murayama T.
    • Journal Title

      Eur J Pharmacol.

      Volume: 764 Pages: 471-479

    • DOI

      10.1016/j.ejphar.2015.07.042

    • Related Report
      2015 Annual Research Report
    • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
  • [Journal Article] Cellular density-dependnet down-regulation of EP4 prostanoid receptors via the up-regulation of hypoxia-inducible factor-1α in HCA-7 human colon cancer cells.2015

    • Author(s)
      Otake S, Yoshida K, Seira N, Sanchez CM, Regan JW, Fujino H, Murayama T.
    • Journal Title

      Pharmacol Res Perspect.

      Volume: 3 Issue: 1

    • DOI

      10.1002/prp2.83

    • Related Report
      2014 Research-status Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Journal Article] Human EP2 prostanoid receptors exhibit more constraints to mutations than human DP prostanoid receptors.2015

    • Author(s)
      Tanimoto J, Fujino H, Takahashi H, Murayama T.
    • Journal Title

      FEBS Lett.

      Volume: 589 Issue: 6 Pages: 766-772

    • DOI

      10.1016/j.febslet.2015.02.006

    • Related Report
      2014 Research-status Report
    • Peer Reviewed / Acknowledgement Compliant
  • [Journal Article] Hydrogen sulfide-mediated regulation of contractility in the mouse ileum with electrical stimulation: roles of L-cysteine, cystathionine β-synthase, and K+ channels.2014

    • Author(s)
      Yamane S, Kanno T, Nakamura H, Fujino H, Murayama T.
    • Journal Title

      Eur J Pharmacol

      Volume: 740 Pages: 112-120

    • DOI

      10.1016/j.ejphar.2014.06.054

    • Related Report
      2014 Research-status Report
    • Peer Reviewed
  • [Journal Article] TRPM8 has a key role in experimental colitis-induced visceral hyperalgesia in mice2014

    • Author(s)
      Hosoya T, Matsumoto K, Tashima K, Nakamura H, Fujino H, Murayama T, Horie S
    • Journal Title

      Neurogastroenterol Motil

      Volume: 印刷中 Issue: 8 Pages: 1112-1121

    • DOI

      10.1111/nmo.12368

    • Related Report
      2014 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] A novel indole compound, AWT-489, inhibits prostaglandin D2-induced CD55 expression by acting on DP prostanoid receptors as an antagonist in LS174T human colon cancer cells.2014

    • Author(s)
      Oyama S, Fujino H, Yamazaki R, Okura I, Regan JW, Awata A, Arai T, Murayama T.
    • Journal Title

      Arch. Biochem. Biophys.

      Volume: 541 Pages: 21-29

    • DOI

      10.1016/j.abb.2013.10.023

    • Related Report
      2013 Research-status Report
    • Peer Reviewed
  • [Journal Article] Induction of cyclooxygenase-2 expression by prostaglandin E2 stimulation of the prostanoid EP4 receptor via coupling to Gai and transactivation of the epidermal growth factor receptor in HCA-7 human colon cancer cells.2013

    • Author(s)
      Yoshida K, Fujino H, Otake S, Seira N, Regan JW, Murayama T
    • Journal Title

      Eur J Pharmacol

      Volume: 718 Issue: 1-3 Pages: 408-417

    • DOI

      10.1016/j.ejphar.2013.08.002

    • Related Report
      2013 Research-status Report
    • Peer Reviewed
  • [Journal Article] Bee venom phospholipase A2-induced phasic contractions in mouse rectum: Independent roles of eicosanoid and gap junction proteins and their loss in experimental colitis2013

    • Author(s)
      Nomura R, Yanagihara M, Sato H, Matsumoto K, Tashima K, Horie S, Chen S, Fujino H, Ueno K, Murayama T
    • Journal Title

      Eur J Pharmacol

      Volume: 718 Issue: 1-3 Pages: 314-322

    • DOI

      10.1016/j.ejphar.2013.08.015

    • Related Report
      2013 Research-status Report
    • Peer Reviewed
  • [Presentation] ヒト結腸癌HCA-7細胞を用いたヒトEP4プロスタノイド受容体による持続的な新規プロスタグランジンE2産生機構の解明2016

    • Author(s)
      藤野裕道、清良尚史、倉田直希、荒木祐美、中村浩之、John W. Regan、村山俊彦
    • Organizer
      日本薬学会第136年会
    • Place of Presentation
      パシフィコ横浜(神奈川県横浜市)
    • Year and Date
      2016-03-26
    • Related Report
      2015 Annual Research Report
  • [Presentation] ヒト結腸癌HCA-7細胞において、HIF-1αはEP4受容体プロモーターHRE配列に結合し、受容体発現を制御する2016

    • Author(s)
      清良尚史、藤野裕道、大竹翔、John W. Regan、村山俊彦
    • Organizer
      日本薬学会第136年会
    • Place of Presentation
      パシフィコ横浜(神奈川県横浜市)
    • Year and Date
      2016-03-26
    • Related Report
      2015 Annual Research Report
  • [Presentation] シクロスポリンAはヒト肺線維芽細胞および肺線維症モデルマウスにおいて線維化抑制作用を示す2016

    • Author(s)
      山崎璃沙、藤田哲雄、柳原まどか、中村浩之、藤野裕道、粕谷善俊、村山俊彦
    • Organizer
      日本薬学会第136年会
    • Place of Presentation
      パシフィコ横浜(神奈川県横浜市)
    • Year and Date
      2016-03-26
    • Related Report
      2015 Annual Research Report
  • [Presentation] 新規インドール化合物のヒト結腸がんLS174T細胞への抗がん作用の探索2016

    • Author(s)
      柳澤直樹、藤野裕道、和才真希子、荒井孝義、村山俊彦
    • Organizer
      第89回日本薬理学会年会
    • Place of Presentation
      パシフィコ横浜(神奈川県横浜市)
    • Year and Date
      2016-03-09
    • Related Report
      2015 Annual Research Report
  • [Presentation] ヒトDPおよびEP2プロスタノイド受容体のcDNA配列変異の解析2016

    • Author(s)
      谷本淳、藤野裕道、樋坂章博、高橋弘喜、村山俊彦
    • Organizer
      第89回日本薬理学会年会
    • Place of Presentation
      パシフィコ横浜(神奈川県横浜市)
    • Year and Date
      2016-03-09
    • Related Report
      2015 Annual Research Report
  • [Presentation] ヒトEP4プロスタノイド受容体細胞内ループ3のシグナル伝達系への影響2015

    • Author(s)
      清良尚史、藤野裕道、倉田直希、荒木祐美、村山俊彦
    • Organizer
      第133回日本薬理学会関東部会
    • Place of Presentation
      柏の葉カンファレンスセンター(千葉県柏市)
    • Year and Date
      2015-10-10
    • Related Report
      2015 Annual Research Report
  • [Presentation] Gi型Gタンパク質共役機構を中心としたヒトEP4プロスタノイド受容体細胞内C末端領域の役割の解明2015

    • Author(s)
      倉田直希、藤野裕道、清良尚史、村山俊彦
    • Organizer
      第133回日本薬理学会関東部会
    • Place of Presentation
      柏の葉カンファレンスセンター(千葉県柏市)
    • Year and Date
      2015-10-10
    • Related Report
      2015 Annual Research Report
  • [Presentation] ニーマン・ピック病C型におけるセラミド代謝と細胞内コレステロール輸送との関わり2015

    • Author(s)
      中村浩之、藤野裕道、村山俊彦
    • Organizer
      第14回生命科学研究会
    • Place of Presentation
      三浦市民ホール(神奈川県三浦市)
    • Year and Date
      2015-06-26
    • Related Report
      2015 Annual Research Report
  • [Presentation] がん増悪化情報伝達系へのプロスタノイド受容体の役割2015

    • Author(s)
      藤野裕道
    • Organizer
      日本薬学会第135年会
    • Place of Presentation
      神戸
    • Year and Date
      2015-03-25 – 2015-03-28
    • Related Report
      2014 Research-status Report
    • Invited
  • [Presentation] TGF-β1による肺線維化への免疫抑制剤の影響2015

    • Author(s)
      山崎璃沙、松澤康雄、川島辰男、柳原まどか、中村浩之、藤野裕道、村山俊彦
    • Organizer
      日本薬学会第135年会
    • Place of Presentation
      神戸
    • Year and Date
      2015-03-25 – 2015-03-28
    • Related Report
      2014 Research-status Report
  • [Presentation] ヒトEP4プロスタノイド受容体細胞内ループ3のT cell Factor転写活性への影響2015

    • Author(s)
      清良尚史、藤野裕道、倉田直希、Regan JW、村山俊彦
    • Organizer
      日本薬学会第135年会
    • Place of Presentation
      神戸
    • Year and Date
      2015-03-25 – 2015-03-28
    • Related Report
      2014 Research-status Report
  • [Presentation] Evans Blue処置による摘出腸管標本への影響:giant contractionsの発生2015

    • Author(s)
      菅野敏生、陳爍楠、藤野裕道、村山俊彦
    • Organizer
      日本薬学会第135年会
    • Place of Presentation
      神戸
    • Year and Date
      2015-03-25 – 2015-03-28
    • Related Report
      2014 Research-status Report
  • [Presentation] ヒト結腸癌HCA-7細胞の細胞密度依存的なEP4プロスタノイド受容体発現量の減少2015

    • Author(s)
      藤野裕道、大竹翔、吉田憲司、清良尚史、Chistopher MS、Regan JW、村山俊彦
    • Organizer
      第88回日本薬理学会
    • Place of Presentation
      名古屋
    • Year and Date
      2015-03-18 – 2015-03-20
    • Related Report
      2014 Research-status Report
  • [Presentation] プロスタグランジンD2はEP2プロスタノイド受容体を介してcAMP非依存的にT cell factorシグナルを活性化する2015

    • Author(s)
      大蔵伊織、藤野裕道、清良尚史、Christopher MS、Regan JW、村山俊彦
    • Organizer
      第88回日本薬理学会
    • Place of Presentation
      名古屋
    • Year and Date
      2015-03-18 – 2015-03-20
    • Related Report
      2014 Research-status Report
  • [Presentation] ヒトEP4プロスタノイド受容体C末端領域機能の解明2014

    • Author(s)
      清良尚史、藤野裕道、谷本淳、Regan JW、村山俊彦
    • Organizer
      第131回日本薬理学会関東部会
    • Place of Presentation
      横浜
    • Year and Date
      2014-10-11
    • Related Report
      2014 Research-status Report
  • [Presentation] Contrary effects of sphingosine-1-phosphate on expression of α-smooth muscle actin in transforming growth factor β1-stimulated lung fibroblasts.2014

    • Author(s)
      Yamazaki R, Kawashima T, Matsuzawa Y, Otake S, Yamaura E, Nakamura H, Fujino H, Murayama T.
    • Organizer
      54th International Conference on the Bioscience of Lipids 2014
    • Place of Presentation
      Aberdeen, Scotland, UK
    • Year and Date
      2014-06-23 – 2014-06-27
    • Related Report
      2014 Research-status Report
  • [Presentation] ラクトシルセラミドによる細胞質型ホスホリパーゼA2α活性化機構の解明2014

    • Author(s)
      中村浩之、森山友太、藤野裕道、村山俊彦
    • Organizer
      第13回 生命科学研究会
    • Place of Presentation
      札幌
    • Year and Date
      2014-06-20 – 2014-06-21
    • Related Report
      2014 Research-status Report
  • [Presentation] ヒト結腸癌HCA-7細胞におけるEP4受容体発現とhypoxia inducible factor-1α発現との関連性の解明2014

    • Author(s)
      清良尚史、藤野裕道、大竹翔、吉田憲司、Regan JW、村山俊彦
    • Organizer
      日本薬学会第134年会
    • Place of Presentation
      熊本
    • Related Report
      2013 Research-status Report
  • [Presentation] 新規インドール化合物AWT-489はプロスタノイド受容体にアンタゴニストとして作用しCD55発現を抑制する2014

    • Author(s)
      藤野裕道、大山聡美、山崎璃沙、大藏伊織、Regan JW、阿波田篤子、荒井孝義、村山俊彦
    • Organizer
      第87回日本薬理学会年会
    • Place of Presentation
      仙台
    • Related Report
      2013 Research-status Report
  • [Presentation] 肺線維化への免疫抑制剤の影響2014

    • Author(s)
      山崎璃沙、松澤康雄、川島辰男、柳原まどか、中村浩之、藤野裕道、村山俊彦
    • Organizer
      第87回日本薬理学会年会
    • Place of Presentation
      仙台
    • Related Report
      2013 Research-status Report
  • [Presentation] 細胞内コレステロール輸送に関するスフィンゴミエリンの関与2013

    • Author(s)
      鰐川雅裕、中村浩之、藤野裕道、村山俊彦
    • Organizer
      第57回日本薬学会関東支部大会
    • Place of Presentation
      東京
    • Related Report
      2013 Research-status Report
  • [Presentation] TGF-β1による肺線維化への免疫抑制剤への影響2013

    • Author(s)
      山崎璃沙、松澤康雄、川島辰男、柳原まどか、中村浩之、藤野裕道、村山俊彦
    • Organizer
      第128回日本薬理学会関東支部会
    • Place of Presentation
      東京
    • Related Report
      2013 Research-status Report
  • [Presentation] ヒト結腸癌細胞HCA-7細胞においてEP4受容体はGiαタンパク質/上皮成長因子受容体を介してシクロオキシゲナーゼ-2発現を亢進する2013

    • Author(s)
      藤野裕道、吉田憲司、中村浩之、Regan JW、村山俊彦
    • Organizer
      第12回生命科学研究会
    • Place of Presentation
      青森
    • Related Report
      2013 Research-status Report
  • [Remarks] 薬効薬理学ホームページ 千葉大学大学院薬学研究院・薬学部

    • URL

      http://www.p.chiba-u.jp/lab/hinka/index.html

    • Related Report
      2015 Annual Research Report
  • [Remarks] 薬効薬理学ホームページ 千葉大学大学院薬学研究院・薬学部

    • URL

      http://www.p.chiba-u.jp/lab/hinka/

    • Related Report
      2014 Research-status Report
  • [Remarks] 薬効薬理学ホームページ - 千葉大学大学院薬学研究院・薬学部

    • URL

      http://www.p.chiba-u.ac.jp/lab/hinka/

    • Related Report
      2013 Research-status Report
  • [Patent(Industrial Property Rights)] インドール化合物、DPプロスタノイド受容体アンタゴニスト、それを用いた薬剤、及びDPプロスタノイド受容体アンタゴニストの使用2013

    • Inventor(s)
      荒井孝義、藤野裕道、村山俊彦、大山聡美、阿波田篤子
    • Industrial Property Rights Holder
      国立大学法人千葉大学
    • Industrial Property Rights Type
      特許
    • Industrial Property Number
      2013-192422
    • Filing Date
      2013-09-17
    • Related Report
      2013 Research-status Report

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Published: 2014-07-25   Modified: 2022-01-27  

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