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Proteome changes associated with effect of high-dose single-fractionation radiation on lung adenocarcinoma cell lines

ABSTRACT: Lung cancer is a leading cause of cancer-related mortality globally, with non-small cell lung cancer (NSCLC) representing 85% of cases. Advances in treatment modalities, including the emergence of antibody-drug conjugates and stereotactic radiation therapy, have improved outcomes. However, the possible synergistic effects of these therapies remain underexplored at the molecular level. This study investigated high-dose radiation-induced proteomic changes in lung adenocarcinoma cell line HCC-44 grown adherently and cell line A549, grown as adherent cells and 3D spheroids. Our hypothesis was that proteins upregulated by 10 Gy irradiation serve as resistance drivers in cancerous cells and can thus represent potential therapeutic targets.The label-free mass spectrometry revealed distinct proteomic responses to 10 Gy irradiation, varying by cell line and culture conditions. Differentially expressed proteins elevated in the irradiated samples included ephrin type-A receptor 2 (EPHA2) in adherent cells and insulin-like growth factor 2 receptor (IGF2R), tetraspanin 3 (TSPAN3) as well as cathepsin D (CTSD) in spheroids. The validation of these targets was carried out via Western blot, immunofluorescence, viability assay and spheroid formation assay. The functional assays demonstrated that irradiation sensitized A549 cells to EPHA2 and CTSD inhibitors. These findings underscore the potential of integrating radiation and targeted therapies in NSCLC treatment, and highlight EPHA2 as a promising candidate for future therapeutic strategies.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Lung, Epithelial Cell, Cell Culture

DISEASE(S): Non-small Cell Lung Carcinoma

SUBMITTER: Darja Lavogina

LAB HEAD: Jana Jaal

PROVIDER: PXD057576 | Pride | 2025-07-06

REPOSITORIES: Pride

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			Action	DRS
	240429_04_Orbi3_MS_QC_G120_T150_Lav6gina_A549_sph_10_Gy_EXP3_2ug.raw	Raw
	240429_06_Orbi3_MS_QC_G120_T150_Lav6gina_HCC_44_2D_NT_EXP2_2ug.raw	Raw
	240429_08_Orbi3_MS_QC_G120_T150_Lav6gina_HCC_44_2D_10_Gy_EXP2_2ug.raw	Raw
	240429_10_Orbi3_MS_QC_G120_T150_Lav6gina_A549_2D_10_Gy_EXP2_2ug.raw	Raw
	240429_12_Orbi3_MS_QC_G120_T150_Lav6gina_A549_2D_NT_EXP2_2ug.raw	Raw

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Project description:Cancer-associated fibroblasts (CAFs) are acknowledged key determinants in the progression of cancer and thereby represent important targets for cancer therapies. Given the increase attention that ablative radiotherapy is gaining in the clinics, in this study we have aimed at identifying the transcriptional responses occurring in primary CAFs exposed to high-dose irradiation. Established primary cancer-associated fibroblasts (CAFs) obtained from non-small-cell lung cancer (NSCLC) patient material were irradiated with a single dose of 18 Gy and total RNA was isolated 24 hrs after treatment. Radiation-induced transcriptional alterations were investigated by gene expression analysis using genome-wide microarrays. Obtained results were verified by qRT-PCR of relevant genes. To confirm the data achieved by microarrays, diverse functional assays were performed including DNA damage response foci assay, measurements of reactive oxygen species (ROS) by flow cytometry and senescence-associated beta-galactosidase assays were applied. Irradiation resulted in differential expression of 680 genes of which 553 were up- and 127 down-regulated. 153 genes were differentially expressed with a fold-change greater than 1 and an adjusted p-value less than 0.05 across different comparisons (non-irradiated vs. irradiated). Expression patterns revealed profound changes in biological functions and processes involved in DNA repair, apoptosis, p53 pathway, autophagy, senescence, ROS production and immune response. Conclusions: CAFs display pro- and anti-tumorigenic effects after having received a single high-dose radiation. The effects might have an impact on the tumor microenvironment in respect to tumor growth and metastasis. The complexity of the observed differential gene expression patterns and implicative biological effects are interesting future objectives for further elucidation. Established primary cancer-associated fibroblasts (CAFs) obtained from non-small-cell lung cancer (NSCLC) patient material were irradiated with a single dose of 18 Gy and total RNA was isolated 24 hrs after treatment.

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Proteome changes associated with effect of high-dose single-fractionation radiation on lung adenocarcinoma cell lines

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