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Targeting ATP13A4-polyamine homeostasis axis to improve radiosensitivity of lung adenocarcinoma
Aoyun Yan1, Xiaoyan Han2, Shijia Wang1
1Teaching and Research Section of Nuclear Medicine, School of Basic Medicine, Anhui Medical University, Hefei, Anhui Province, 230032, China.
Abstract:
The radioresistance of lung adenocarcinoma poses a major challenge to radiotherapy efficacy, yet its underlying mechanisms remain poorly defined. ATP13A4, a member of the P5B-type ATPase family, plays an important role in brain function and neurodevelopmental disorders. While recent studies have highlighted its role in breast cancer, its function in lung adenocarcinoma remains unclear. Our bioinformatics analysis revealed that ATP13A4 expression declines with disease progression in lung adenocarcinoma tissues, correlating with unfavorable patient prognosis. Overexpression of ATP13A4 suppressed tumor growth, cell invasion, migration, and epithelial-mesenchymal transition. Notably, ATP13A4 overexpression markedly sensitized lung adenocarcinoma cells to radiation. Mechanistically, we found that ATP13A4 disrupted polyamine homeostasis. Its overexpression increased the overall polyamine pool size while concurrently accelerating the turnover of spermidine and spermine. This metabolic reprogramming ultimately enhanced the cell's sensitivity to ferroptosis, leading to a significant increase in cell death after X-ray irradiation. Our findings unveiled ATP13A4 as a key metabolic regulator in lung adenocarcinoma and proposed targeting the polyamine-ferroptosis axis as a promising strategy to improve radiosensitivity.
Insights
Lung adenocarcinoma cells become more sensitive to radiation therapy when ATP13A4 is overexpressed. This protein regulates polyamine metabolism, enhancing ferroptosis and improving treatment outcomes.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Radiotherapy resistance is a significant hurdle in treating lung adenocarcinoma.
- The precise mechanisms driving radioresistance are not fully understood.
- ATP13A4's role in lung adenocarcinoma is largely unexplored, despite its known functions in other cancers and brain development.
Purpose of the Study:
- To investigate the role of ATP13A4 in lung adenocarcinoma radioresistance.
- To elucidate the molecular mechanisms by which ATP13A4 influences tumor behavior and radiation sensitivity.
- To explore the potential of targeting the polyamine-ferroptosis pathway for improved lung adenocarcinoma treatment.
Main Methods:
- Bioinformatics analysis of ATP13A4 expression in lung adenocarcinoma tissues.
- In vitro studies involving ATP13A4 overexpression in lung adenocarcinoma cell lines.
- Assessment of tumor growth, invasion, migration, and epithelial-mesenchymal transition.
- Analysis of polyamine metabolism and ferroptosis induction.
- Evaluation of radiosensitization effects following X-ray irradiation.
Main Results:
- ATP13A4 expression decreases with lung adenocarcinoma progression and correlates with poor prognosis.
- Overexpression of ATP13A4 inhibits tumor growth, invasion, migration, and epithelial-mesenchymal transition.
- ATP13A4 overexpression significantly sensitizes lung adenocarcinoma cells to radiation.
- ATP13A4 disrupts polyamine homeostasis, increasing polyamine pool size and accelerating spermidine/spermine turnover.
- This metabolic shift enhances ferroptosis sensitivity, leading to increased cell death upon irradiation.
Conclusions:
- ATP13A4 acts as a critical metabolic regulator in lung adenocarcinoma.
- Targeting the polyamine-ferroptosis axis presents a novel strategy to enhance radiosensitivity in lung adenocarcinoma.
- ATP13A4 holds potential as a therapeutic target for overcoming radiotherapy resistance.
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