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The study of the mechanism by which anti-cancer drugs induce EMT

Research Project

Project/Area Number 20K05732
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Review Section Basic Section 37020:Chemistry and chemical methodology of biomolecules-related
Research InstitutionShowa Pharmaceutical University

Principal Investigator

Tashiro Etsu  昭和薬科大学, 薬学部, 准教授 (00365446)

Project Period (FY) 2020-04-01 – 2023-03-31
Project Status Completed (Fiscal Year 2022)
Budget Amount *help
¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Fiscal Year 2022: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2021: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2020: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Keywords制がん剤耐性 / EMT / TGF-b / TGF-beta / シスプラチン / 上皮間葉転換
Outline of Research at the Start

CDDPによるEMT誘導過程の分子機序を明らかにするため、CDDP添加後のEMTマーカー分子の発現挙動を時系列で測定する。続いて各種シグナル伝達阻害剤、さらにはEMT誘導転写因子のノックダウンがEMTマーカー分子の発現に与える影響を評価することで、CDDPによるEMT誘導のパスウェイを描画する。
また、作用機序の異なる制がん剤と遺伝背景の異なるがん細胞の組み合わせに対して、上記で使用した各種シグナル伝達阻害剤やEMT転写因子のノックダウンの影響も検出し、こられを数値化、クラスター解析することで、EMT誘導機構の普遍性・多様性を明らかにする

Outline of Final Research Achievements

We found that long-term exposure of colorectal cancer LoVo cells to the platinum anticancer drug cisplatin changed the epithelial-like phenotype to the mesenchymal-like phenotype which is a typical feature of EMT (Epithelial-Mesenchymal Transition). Therefore, we tried to examine the mechanism using a chemical genomics approach, and we found that TGF-b receptor inhibitors reversed the mesenchymal phenotype of cisplatin-resistant cells to epithelial phenotypes. These results suggested that the activation of TGF-b signaling plays a critical role in the acquisition of cisplatin-induced drug resistance. Moreover, we found that cisplatin enhanced the secretion of TGF-b into the culture medium. Taken together, it is suggested that cisplatin enhances the secretion of TGF-b, which resulted in the activation of TGF-b signaling and thereby inducing EMT and subsequent drug resistance.

Academic Significance and Societal Importance of the Research Achievements

制がん剤を暴露し続けると制がん剤耐性を獲得することは古くから知られており、解決すべき問題の一つである。近年、制がん剤耐性とEMTの関連が明らかになり、申請者らが独自で行った実験でも、制がん剤耐性細胞でEMTが誘導されていることが再現できた。そしてそのメカニズムの一つとして、EMTを強力に誘導するTGF-bの分泌促進という新しいモデルを提唱できたことが本研究の学術的意義である。TGF-bシグナルの阻害剤は幾つか開発されており、それらが制がん剤耐性を獲得した実際のがん患者に応用され、効果が発揮されることを期待する。

Report

(4 results)
  • 2022 Annual Research Report   Final Research Report ( PDF )
  • 2021 Research-status Report
  • 2020 Research-status Report
  • Research Products

    (14 results)

All 2022 2021 2020

All Journal Article (11 results) (of which Int'l Joint Research: 1 results,  Peer Reviewed: 11 results,  Open Access: 3 results) Presentation (2 results) (of which Int'l Joint Research: 2 results) Book (1 results)

  • [Journal Article] Isolation of caldorazole, a thiazole-containing polyketide with selective cytotoxicity under glucose-restricted conditions2022

    • Author(s)
      Osamu Ohno, Arihiro Iwasaki, Kyouhei Same, Chihiro Kudo, Erika Aida, Kazuya Sugiura, Shimpei Sumimoto, Toshiaki Teruya, Etsu Tashiro, Siro Simizu, Kenji Matsuno, Masaya Imoto, Kiyotake Suenaga
    • Journal Title

      Organic Letters

      Volume: 24 Issue: 25 Pages: 4547-4551

    • DOI

      10.1021/acs.orglett.2c01566

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Bisprenyl naphthoquinone and chlorinated calcimycin congener bearing thiazole ring from an actinomycete of the genus Phytohabitans2022

    • Author(s)
      Harunari Enjuro、Mae Shunsuke、Fukaya Keisuke、Tashiro Etsu、Urabe Daisuke、Igarashi Yasuhiro
    • Journal Title

      The Journal of Antibiotics

      Volume: 75 Issue: 10 Pages: 542-551

    • DOI

      10.1038/s41429-022-00559-x

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Phytohabitols A-C, δ-lactone-terminated polyketides from an actinomycete of the genus Phytohabitans2022

    • Author(s)
      S. Saito, Y. Xiaohanyao, T. Zhou, J. Nakajima-Shimada, E. Tashiro, D. W. Triningsih, E. Harunari, N. Oku, Y. Igarashi
    • Journal Title

      Journal of Natural Products

      Volume: 85 Issue: 7 Pages: 1697-1703

    • DOI

      10.1021/acs.jnatprod.2c00137

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Hybrid molecule between platanic acid and LCL-161 as a yes-associated protein degrader2022

    • Author(s)
      Nakano Naoko、Fukuda Kazuo、Tashiro Etsu、Ishikawa Haruka、Nagano Waka、Kawamoto Rie、Mori Alice、Watanabe Misao、Yamazaki Ryu、Nakane Takahisa、Naito Mikihiko、Okamoto Iwao、Itoh Susumu
    • Journal Title

      The Journal of Biochemistry

      Volume: - Issue: 6 Pages: 631-640

    • DOI

      10.1093/jb/mvac021

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Involvement of miR-3180-3p and miR-4632-5p in palmitic acid-induced insulin resistance2021

    • Author(s)
      Tashiro Etsu、Nagasawa Yumi、Itoh Susumu、Imoto Masaya
    • Journal Title

      Molecular and Cellular Endocrinology

      Volume: 534 Pages: 111371-111371

    • DOI

      10.1016/j.mce.2021.111371

    • Related Report
      2021 Research-status Report
    • Peer Reviewed
  • [Journal Article] Androgen receptor antagonists produced by Streptomyces overcome resistance to enzalutamide2021

    • Author(s)
      Imoto M, Fujimaki T, Saito S, Tashiro E.
    • Journal Title

      J. Antibiot.

      Volume: 74 Issue: 10 Pages: 706-716

    • DOI

      10.1038/s41429-021-00453-y

    • Related Report
      2021 Research-status Report
    • Peer Reviewed
  • [Journal Article] Narciclasine is a novel YAP inhibitor that disturbs interaction between YAP and TEAD42021

    • Author(s)
      Kawamoto R, Nakano N, Ishikawa H, Tashiro E, Nagano W, Sano K, Irie M, Ikuta M, Kishi F, Nakane T, Naito M, Itoh S.
    • Journal Title

      BBA Advances

      Volume: 1 Pages: 100008-100008

    • Related Report
      2021 Research-status Report
    • Peer Reviewed
  • [Journal Article] Cyclopeptides from the Mushroom Pathogen Fungus Cladobotryum varium2021

    • Author(s)
      Zhou Tao、Katsuragawa Misaki、Xing Tian、Fukaya Keisuke、Okuda Toru、Tokiwa Toshiyuki、Tashiro Etsu、Imoto Masaya、Oku Naoya、Urabe Daisuke、Igarashi Yasuhiro
    • Journal Title

      Journal of Natural Products

      Volume: 84 Issue: 2 Pages: 327-338

    • DOI

      10.1021/acs.jnatprod.0c00980

    • Related Report
      2020 Research-status Report
    • Peer Reviewed
  • [Journal Article] A chemical genomics-aggrephagy integrated method studying functional analysis of autophagy inducers2020

    • Author(s)
      Kataura Tetsushi、Tashiro Etsu、Nishikawa Shota、Shibahara Kensuke、Muraoka Yoshihito、Miura Masahiro、Sakai Shun、Katoh Naohiro、Totsuka Misato、Onodera Masafumi、Shin-Ya Kazuo、Miyamoto Kengo、Sasazawa Yukiko、Hattori Nobutaka、Saiki Shinji、Imoto Masaya
    • Journal Title

      Autophagy

      Volume: Aug 7 Issue: 8 Pages: 1-17

    • DOI

      10.1080/15548627.2020.1794590

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Interaction between goniothalamin and peroxisomal multifunctional enzyme type 2 triggering endoplasmic reticulum stress2020

    • Author(s)
      Sophonnithiparasert T, Aruksakunwong O, Tashiro E, Kondoh Y, Muroi M, Osada H, Imoto M, Watanapokasin R
    • Journal Title

      Heliyon

      Volume: 6 Issue: 10 Pages: e05200-e05200

    • DOI

      10.1016/j.heliyon.2020.e05200

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Generation of incednine derivatives by mutasynthesis2020

    • Author(s)
      Miyanaga A, Takaku R, Takaishi M, Tashiro E, Kudo F, Eguchi T
    • Journal Title

      Th Journal of Antibiotics

      Volume: 73 Issue: 11 Pages: 794-797

    • DOI

      10.1038/s41429-020-0329-y

    • Related Report
      2020 Research-status Report
    • Peer Reviewed
  • [Presentation] Involvement of TGF-beta signal activation in anti-cancer drug resistance2022

    • Author(s)
      Etsu Tashiro, Masaya Imoto, Susumu Itoh
    • Organizer
      FASEB SRC; The TGF-beta Superfamily Conference: Signaling in Development and Disease
    • Related Report
      2022 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Involvement of mitogen and stress activated protein kinase (MSK1)1 in BMP-induced chondrocyte differentiation2022

    • Author(s)
      Susumu Itoh, Naoko Nakano, Etsu Tashiro
    • Organizer
      13th BMP Conference 2022
    • Related Report
      2022 Annual Research Report
    • Int'l Joint Research
  • [Book] マウス・ラットモデル作製・解析プロフェッショナル2021

    • Author(s)
      先端モデル動物支援プラットフォーム(AdAMS)
    • Total Pages
      320
    • Publisher
      羊土社
    • ISBN
      9784758121125
    • Related Report
      2020 Research-status Report

URL: 

Published: 2020-04-28   Modified: 2024-01-30  

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