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Macrophage Resistance to Ionizing Radiation Exposure Is Accompanied by Decreased Cathepsin D and Increased Transferrin Receptor 1 Expression

2022; Multidisciplinary Digital Publishing Institute; Volume: 15; Issue: 1 Linguagem: Inglês

10.3390/cancers15010270

2072-6694

Ana Teresa Pinto, Ana Beatriz Machado, Hugo Osório, Marta L. Pinto, Rui Vitorino, Gonçalo C. Justino, Cátia Santa, Flávia Castro, Tânia Cruz, Carla Rodrigues, Jorge Lima, José Sousa, Ana Patrícia Cardoso, Rita de Cassia Sávio Figueira, Armanda Monteiro, Margarida Marques, Bruno Manadas, Jarne Pauwels, Kris Gevaert, Marc Mareel, Sónia Rocha, Tiago L. Duarte, Maria José Oliveira,

Nuclear Structure and Function

Purpose: To identify a molecular signature of macrophages exposed to clinically relevant ionizing radiation (IR) doses, mirroring radiotherapy sessions. Methods: Human monocyte-derived macrophages were exposed to 2 Gy/ fraction/ day for 5 days, mimicking one week of cancer patient’s radiotherapy. Protein expression profile by proteomics was performed. Results: A gene ontology analysis revealed that radiation-induced protein changes are associated with metabolic alterations, which were further supported by a reduction of both cellular ATP levels and glucose uptake. Most of the radiation-induced deregulated targets exhibited a decreased expression, as was the case of cathepsin D, a lysosomal protease associated with cell death, which was validated by Western blot. We also found that irradiated macrophages exhibited an increased expression of the transferrin receptor 1 (TfR1), which is responsible for the uptake of transferrin-bound iron. TfR1 upregulation was also found in tumor-associated mouse macrophages upon tumor irradiation. In vitro irradiated macrophages also presented a trend for increased divalent metal transporter 1 (DMT1), which transports iron from the endosome to the cytosol, and a significant increase in iron release. Conclusions: Irradiated macrophages present lower ATP levels and glucose uptake, and exhibit decreased cathepsin D expression, while increasing TfR1 expression and altering iron metabolism.