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

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This document discusses the dysfunction of FBXL5-mediated ferrous iron homeostasis and its impact on lung cancer growth. Iron is an essential mineral for all living organisms, existing in two oxidation states: ferrous iron (Fe2) and ferric iron (Fe3). The FBXL5/IRP2 axis is responsible for maintaining iron valent homeostasis. The study aimed to explore the significance of iron valence change in lung cancer by genetically modulating the FBXL5/IRP2 axis in mouse lung cancer.<br /><br />Using Lewis lung carcinoma (LLC) cells, the researchers genetically deleted FBXL5 and IRP2 using the CRISPR-Cas9 system. FBXL5 knockout (KO) cells showed constitutive IRP2 accumulation and elevated ferrous iron levels. The cells with ferrous iron accumulation suppressed cell growth in colony formation assays. In contrast, the depletion of IRP2, leading to ferric iron accumulation, did not suppress growth. This suggests that ferrous iron, but not ferric iron, plays a suppressive role in lung cancer cell growth.<br /><br />In animal experiments, FBXL5 KO cells resulted in smaller tumor masses and improved survival in tumor-bearing mice. FBXL5 mRNA expression in stage I-IV non-small cell lung cancer (NSCLC) patients was examined, revealing that low FBXL5 expression was associated with better prognosis.<br /><br />Cell cycle analysis showed that FBXL5 KO cells had a higher proportion of cells in the G1 phase and a lower proportion in the S phase, indicating impaired G1/S transition. The accumulation of p27, a cyclin-dependent kinase inhibitor, was increased in FBXL5 KO cells. It was found that p27 accumulation was associated with reduced Rb phosphorylation and G1/S delay. Additionally, intracellular reactive oxygen species (ROS) levels were higher in FBXL5 KO cells, suggesting a role for increased ROS in p27 accumulation.<br /><br />In conclusion, dysfunction in ferrous iron homeostasis due to FBXL5 deletion suppresses lung cancer cell growth. The study also highlights the association between ferrous iron and G1/S transition delay caused by p27 accumulation. Targeting FBXL5 to increase intracellular ferrous iron levels may have potential therapeutic benefits for lung cancer treatment.

Asset Subtitle

Hironori Hinokuma

Meta Tag

Speaker Hironori Hinokuma

Topic Tumor Biology: Preclinical Biology - Molecular Therapeutic Targets

Keywords

FBXL5-mediated ferrous iron homeostasis

lung cancer growth

iron valent homeostasis

FBXL5/IRP2 axis

ferrous iron accumulation

ferric iron accumulation

tumor masses

prognosis

G1/S transition

p27 accumulation