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Role of acidosis in hypoxia-induced epithelial mesenchymal transition in lung cancer cells

Research Project

Project/Area Number 21K08189
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Review Section Basic Section 53030:Respiratory medicine-related
Research InstitutionTokyo Medical University

Principal Investigator

Aoshiba Kazutetsu  東京医科大学, 医学部, 教授 (60231776)

Project Period (FY) 2021-04-01 – 2024-03-31
Project Status Completed (Fiscal Year 2023)
Budget Amount *help
¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000)
Fiscal Year 2023: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2022: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2021: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Keywords肺癌 / 低酸素 / アシドーシス / 上皮間葉転換 / マイトファジー / アジスロマイシン / フェノフィブラート / E-カドヘリン / 乳酸
Outline of Research at the Start

癌細胞は低酸素、低栄養、アシドーシスなどの環境ストレスに適応して生存しているが、アシドーシスに対する適応機序については不明な点が多い。本研究課題ではアシドーシスが肺癌細胞の浸潤と転移に与える影響とその制御法を検討するために、低酸素曝露による上皮間葉転換 (Epithelial mesenchymal transition: EMT)を介した肺癌細胞の浸潤と転移におけるアシドーシスの役割を明らかにする。予備実験においては肺癌細胞の低酸素曝露によるEMTがアシドーシスの中和によりほぼ完全に抑制されたことから、アシドーシス制御による低酸素曝露EMTの抑制法の開発を目指す。

Outline of Final Research Achievements

We investigated the effect of hypoxic acidosis on epithelial mesenchymal transition (EMT) in lung cancer cells. We found that exposure of lung cancer cells to hypoxia caused EMT; however, it was almost completely inhibited by neutralization of acidic pH in medium. The mechanisms by which acidosis enhanced hypoxia-induced EMT included the reduction of E-cadherin protein, which was caused by decreased production of E-cadherin mRNA and increased degradation of E-cadherin protein via its ubiquitination. We also found that the azithromycin, a macrolide antibiotic, reduced lung cancer cell survival under hypoxic conditions by interfering with the efficient removal of damaged mitochondria through mitophagy inhibition. Finally, we found that fenofibrate, an anti-hyperlipidemic drug, attenuated cisplatin cytotoxicity to lung cancer cells by enhancing the antioxidant defense system through activation of nuclear factor erythroid 2 related factor 2.

Academic Significance and Societal Importance of the Research Achievements

腫瘍内部の低酸素は肺癌細胞の浸潤、転移や進行を促進する要因であるが、その対処法として低酸素に伴うアシドーシス是正による上皮間葉転換の抑制や抗菌薬であるアジスロマイシンによるマイトファジー抑制によるアポトーシスの誘導が有効であると考えられた。また脂質異常症治療薬であるフェノフィブラートがシスプラチンに対する治療抵抗性を亢進させる可能性が考えられた。

Report

(4 results)
  • 2023 Annual Research Report   Final Research Report ( PDF )
  • 2022 Research-status Report
  • 2021 Research-status Report
  • Research Products

    (3 results)

All 2023 2022

All Journal Article (2 results) (of which Peer Reviewed: 2 results,  Open Access: 1 results) Presentation (1 results)

  • [Journal Article] <i>In?vitro</i> anticancer effect of azithromycin targeting hypoxic lung cancer cells via the inhibition of mitophagy2023

    • Author(s)
      Toriyama Kazutoshi、Okuma Takashi、Abe Shinji、Nakamura Hiroyuki、Aoshiba Kazutetsu
    • Journal Title

      Oncology Letters

      Volume: 27 Issue: 1 Pages: 313-313

    • DOI

      10.3892/ol.2023.14146

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Fenofibrate attenuates the cytotoxic effect of cisplatin on lung cancer cells by enhancing the antioxidant defense system in vitro2023

    • Author(s)
      Kogami M, Abe S, Nakamura H, Aoshiba K
    • Journal Title

      Oncology Letters (accepted)

      Volume: -

    • Related Report
      2022 Research-status Report
    • Peer Reviewed
  • [Presentation] フェノフィブラートによるシスプラチンの抗癌作用の減弱効果2022

    • Author(s)
      大野真梨子、阿部信二、中村博幸、青柴和徹
    • Organizer
      第62回日本呼吸器学会総会
    • Related Report
      2022 Research-status Report

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Published: 2021-04-28   Modified: 2025-01-30  

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