Analysis of the mechanism of drug sensitization of cancer cells with cell transition

2022 Fiscal Year Final Research Report

• Project/Area Number: 20K16339
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 50010:Tumor biology-related
• Research Institution: Keio University
• Principal Investigator: Kato Yu 慶應義塾大学, 薬学部(芝共立), 助教 (80847864)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Keywords: 細胞転換 / 上皮間葉転換 / スフェロイド / glutathione peroxidase 4 / glutathione

Outline of Final Research Achievements

Cells undergo cellular transition to adapt to their survival environment. In this study, we investigated the mechanism of variation in drug sensitivity during cell transition using EMT cells that were transduced SLUG and SNAIL in HCT116 cells derived from human colorectal cancer. We found that EMT cells showed high sensitivity to glutathione peroxidase 4 (GPX4) inhibitors. This high sensitivity of EMT cells to RSL3 was associated with a decrease in intracellular glutathione that is a substrate of GPX4. Next, we searched for drugs that are more sensitive to RSL3 in spheroid culture, which is closer to in vivo than in normal culture. Then we found that dBET6, a BET inhibitor, strongly prevented cell growth during spheroid culture. Moreover, dBET6 increased sensitivity to RSL3 in EMT cells in both normal and spheroid culture.

Free Research Field

腫瘍学、分子生物学

Academic Significance and Societal Importance of the Research Achievements

EMTやスフェロイド培養による細胞転換は、がん細胞の薬剤抵抗性を変動させる。本研究では、EMT、スフェロイド培養による細胞転換後の細胞に強い増殖抑制効果を示す薬剤を同定した。これらの薬剤を既存の治療法を合わせることで、細胞転換による薬剤感受性の多様性を克服可能であると考えられた。また、EMT細胞では、RSL3感受性が高く、GPX4阻害時にフェロトーシスが誘導されることを明らかにした。フェロトーシスは抗がん剤や放射線治療などでも誘導されることが報告されており、EMTが誘導された細胞では、抗がん剤や放射線治療とフェロトーシス誘導剤を組み合わせることで既存の治療法が増強可能であると期待される。