2023 World Conference on Lung Cancer (Posters)-EP02.01. Dysfunction of FBXL5-mediated Ferrous Iron Homeostasis Suppresses Lung Cancer Growth

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Iron is an essential mineral for all living organisms, existing in two oxidation states: ferrous iron (Fe2) and ferric iron (Fe3). The significance of iron valence change in lung cancer is still unknown. FBXL5/IRP2 axis maintains iron valent homeostasis, with FBXL5 mediating the degradation of IRP2. Deletion of FBXL5 leads to accumulation of IRP2 and upregulation of ferrous iron levels, while deletion of IRP2 causes ferric iron accumulation. This study aimed to explore the functions of ferrous and ferric iron in lung cancer cell growth.<br /><br />Using the CRISPR-Cas9 system, FBXL5 and IRP2 were genetically deleted in a Lewis lung carcinoma (LLC) cell line. It was found that FBXL5 depletion caused ferrous iron accumulation and inhibited anchorage-independent tumor cell growth. Exogenous FBXL5 reduced ferrous iron levels and recovered tumor cell growth. Furthermore, FBXL5 depletion suppressed tumor cell growth in a mouse subcutaneous injection model and was consistent with data from The Cancer Genome Atlas (TCGA) of non-small cell lung cancer (NSCLC) stage I-IV.<br /><br />Cell cycle analysis revealed that FBXL5 depletion caused cell cycle delay at the G1/S transition and accumulation of the cell cycle regulator p27, which inhibited phosphorylation of Rb. Deletion of p27 recovered tumor cell growth, suggesting its role in the cell cycle delay observed in FBXL5-depleted cells. FBXL5 KO cells also showed higher cellular reactive oxygen species (ROS) levels, and antioxidant treatment partially reduced p27 expression.<br /><br />In conclusion, dysfunction of ferrous iron homeostasis by FBXL5 deletion suppressed lung cancer cell growth. The study highlights the association between ferrous iron and the G1/S transition delay mediated by p27 accumulation. Targeting FBXL5 to increase intracellular ferrous iron may be beneficial for future lung cancer treatments. The findings provide insights into the distinct functions of ferrous and ferric iron in lung cancer cell growth.

Asset Subtitle

Hironori Hinokuma

Meta Tag

Speaker Hironori Hinokuma

Topic Tumor Biology: Preclinical Biology - Molecular Therapeutic Targets

Keywords

iron

oxidation states

ferrous iron

ferric iron

lung cancer

FBXL5

IRP2

iron valence change

ferrous iron accumulation

ferric iron accumulation