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

2023 Fiscal Year Final Research Report

• Project/Area Number: 21K08189
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 53030:Respiratory medicine-related
• Research Institution: Tokyo 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
• 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

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.

Free Research Field

呼吸器内科学

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。