Molecular mechanisms of ferroptosis resistance mediated by calcium signaling and their therapeutic application

2023 Fiscal Year Final Research Report

• Project/Area Number: 21K15539
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 50010:Tumor biology-related
• Research Institution: Japanese Foundation for Cancer Research
• Principal Investigator: SHIRAHAMA Hitomi 公益財団法人がん研究会, がん化学療法センター ゲノム研究部, 研究員 (20838552)
• Project Period (FY): 2021-04-01 – 2024-03-31
• Keywords: フェロトーシス / 細胞密度 / SCD / 脂肪酸代謝 / 脂質代謝 / メラノーマ

Outline of Final Research Achievements

In recent years, several studies have reported that cancer cells show resistance to ferroptosis as cell density increases, but the underlying mechanisms are still largely unknown. In this study, based on the results of preliminary investigations, calcium-mediated signal transduction was primarily investigated. On the other hand, omics analyses comparing low and high cell densities suggested that fatty acid metabolism, especially SCD, is upregulated in high cell density. Indeed, several melanoma cell lines showed an increase in SCD with increasing cell density. Furthermore, sensitization to ferroptosis induction by SCD inhibition was observed at higher cell densities. Thus, SCD was identified as one of the molecules that contribute to ferroptosis resistance at high cell densities.

Free Research Field

腫瘍生物学

Academic Significance and Societal Importance of the Research Achievements

フェロトーシスは比較的最近報告された細胞死の一形態であり、転移性メラノーマをはじめ、複数のがん種がフェロトーシスに脆弱性を示すことから、治療への応用が期待されている。他方で、高細胞密度でフェロトーシス抵抗性があらわれるという報告は、メラノーマのような細胞がひとたび凝集するとフェロトーシス誘導戦略が有効でなくなることを示唆している。本研究ではこの密度依存的なフェロトーシス抵抗性のメカニズム解析に焦点を当て、オミクス解析と生化学実験を通じてSCDがフェロトーシス抵抗性における中心的な役割を果たしていることを明らかにした。この成果は、メラノーマにおける新たながん治療戦略へと繋がることが期待できる。