2424 - PIK3CD Affect Radiotherapy Resistance in LUAD Cells by Reprogramming Lipid Metabolism through PI3K/AKT Pathway
Presenter(s)
Y. Ma1, Y. Xu1, and D. Chen2; 1Shandong Cancer Hospital and Institute, Jinan, Shandong, China, 2Department of Radiation Oncology and Shandong Provincial Key Laboratory of Precision Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China
Purpose/Objective(s): Lung cancer is one of the most prevalent and lethal malignancies globally, with lung adenocarcinoma being the most common histological subtype of non-small cell lung cancer (NSCLC). Radiation therapy is an essential treatment for NSCLC, but radiotherapy resistance impairs its efficacy and worsens prognosis. In this study, we conducted a comprehensive multi-omics analysis of radiotherapy-resistant tumor cells to elucidate their metabolic reprogramming characteristics, thereby identifying potential therapeutic targets for improving radiation therapy efficacy in lung adenocarcinoma.
Materials/Methods: The NSCLC H1299 cells were subjected to multiple consecutive isodose irradiations (2Gy × 30F) using clinically conventional fractionated radiotherapy to establish a radiotherapy-resistant cell line. Transcriptomic sequencing and lipidomic analysis were performed on both parental and resistant cells. Machine learning identified potential prognostic biomarkers for lung adenocarcinoma. A combined lipidomic and transcriptomic analysis was conducted to identify sensitization targets for radiation therapy. The catalytic subunit p110d (PIK3CD) gene expression was validated using Western blot and qRT-PCR, and correlating it with poor prognosis in the TCGA database. Radiation-resistant cell lines with overexpressed PIK3CD genes were analyzed for radiosensitivity via colony formation, cell cycle and cell apoptosis assays. Oil red o staining were performed to detect the lipid content. A subcutaneous tumor model were used to construct the tumor formation assay in BALB/c nude mice.
Results: Lipidomic analyses exhibited alterations in free fatty acids, phosphatidylcholine, and phosphatidylethanolamine in Radiation-resistant cells. A combined lipidomic and transcriptomic analysis showed significant changes in lipid oxidation, degradation, and adipogenesis pathways in Radiation-resistant cells. The PIK3CD of class I PI3K was identified as a key gene which regulating lipid metabolism and radiotherapy sensitivity. Machine learning further identified lipid metabolism-related genes as common biomarkers in Radiation-resistant cells. Further analysis demonstrated that PIK3CD overexpression regulates lung cancer cell growth, proliferation, and survival by phosphorylating phosphatidylinositol lipids and activating the downstream PI3K-AKT-mTOR signaling pathway, which ultimately suppresses the tumor's resistance to radiotherapy.
Conclusion: Lipid metabolism reprogramming contributes to radiotherapy resistance in NSCLC. PIK3CD mediates the PI3K-AKT-mTOR pathway, regulating sensitivity to radiation therapy. This study elucidated the relationship between reprogramming of lipid metabolism and resistance to radiotherapy in NSCLC, providing new perspectives and potential targets for the diagnosis and treatment of lung adenocarcinoma