ATF4/SCO2 Inhibits Ferroptosis in Lung Cancer Through Activating the MAPK Signaling Pathway

Area of Science:

• Oncology
• Cell Biology
• Biochemistry

Background:

• Ferroptosis, a form of regulated cell death driven by iron-dependent lipid peroxidation, plays a critical role in cancer progression.
• Understanding the molecular mechanisms governing ferroptosis is crucial for developing novel lung cancer therapies.

Purpose of the Study:

• To investigate the role and underlying mechanism of ferroptosis in lung cancer.
• To elucidate the relationship between activating transcription factor 4 (ATF4), synthesis of cytochrome c oxidase 2 (SCO2), and the mitogen-activated protein kinases (MAPK) signaling pathway in lung tumorigenesis.

Main Methods:

• Quantitative PCR and Western blotting for gene and protein expression analysis.
• Cell counting kit-8 (CCK-8), transwell, and flow cytometry assays for assessing cell behaviors.
• Measurement of lipid reactive oxygen species (ROS), glutathione (GSH), and Fe2+ to determine ferroptosis.
• Dual-luciferase reporter and chromatin immunoprecipitation assays for binding analysis.
• In vivo studies using a mouse lung cancer model.

Main Results:

• High expression of SCO2 was observed in lung cancer samples and cells, correlating with increased tumorigenesis.
• Downregulation of SCO2 significantly inhibited lung cancer cell growth by inducing ferroptosis.
• ATF4, an upregulated gene in lung cancer, enhances SCO2 expression via promoter binding.
• ATF4 knockdown repressed proliferation and migration while promoting apoptosis and ferroptosis by downregulating SCO2.
• Inhibition of the ATF4/SCO2 axis inactivated the MAPK signaling pathway.

Conclusions:

• ATF4 promotes lung cancer development by upregulating SCO2, which in turn suppresses ferroptosis through activation of the MAPK pathway.
• Targeting the ATF4/SCO2 axis represents a potential therapeutic strategy for lung cancer treatment by inducing ferroptosis.