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Macrophage Resistance to Ionizing Radiation Exposure Is Accompanied by Decreased Cathepsin D and Increased Transferrin Receptor 1 Expression
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Resumo(s)
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.
Descrição
LA/P/0056/2020 and POCI-01-0145-FEDER-31859/2017), the Program “COMPETE Programa Operacional Factores de Competitividade” (FCOMP-01-0124-FEDER-010915) QREN, the European Union (FEDER—Fundo Europeu de Desenvolvimento Regional), Proteostasis COST Action (BM1307), by The National Mass Spectrometry Network (POCI-01-0145-FEDER-402-022125 Ref. ROTEIRO/0028/2013), and the Prize L’Óreal for Women in Science (Foundation L’Óreal/FCT/UNESCO). This work was also funded (in part) by Programa Operacional Regional do Norte and co-funded by European Regional Development Fund under the project “The Porto Comprehensive Cancer Center” with the reference NORTE-01-0145-FEDER-072678–Consórcio PORTO.CCC–Porto Comprehensive Cancer Center Raquel Seruca. Authors also would like to acknowledge also IPATIMUP for the financial support provided through the project: CANCER_CHALLENGE2022, and to International Iberian Nanotechnology Laboratory (INL), and FCT2012-Investigator Program (for MJ Oliveira), EMBO and EACR travel Fellowships, Cancer Research UK (C99667/A12918) and Welcome Trust (097945/B/11/Z) for their grant support.
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© 2022 by the authors.
Palavras-chave
cathepsin D ionizing radiation iron metabolism macrophages proteomics radiotherapy transferrin receptor 1 (TfR1) Oncology Cancer Research SDG 3 - Good Health and Well-being