Fractionated radiation suppresses Kruppel-like factor 2 pathway to a greater extent than by single exposure to the same total dose

Autor: Justin W.C. Leung, Kimberly J. Krager, Ratan Sadhukhan, Alexei G. Basnakian, Rupak Pathak, Sarthak Garg, Alena V. Savenka
Jazyk: angličtina
Rok vydání: 2020
Předmět:
0301 basic medicine
Mef2
Nitric Oxide Synthase Type III
Thrombomodulin
Transcriptional regulatory elements
Kruppel-Like Transcription Factors
lcsh:Medicine
030204 cardiovascular system & hematology
Article
Nitric oxide
Stress signalling
03 medical and health sciences
chemistry.chemical_compound
0302 clinical medicine
Downregulation and upregulation
Enos
Neoplasms
Human Umbilical Vein Endothelial Cells
medicine
Humans
Endothelial dysfunction
lcsh:Science
Mitogen-Activated Protein Kinase 7
Radiation
Multidisciplinary
biology
MEF2 Transcription Factors
Kinase
Chemistry
lcsh:R
Dose-Response Relationship
Radiation
Intercellular Adhesion Molecule-1
medicine.disease
biology.organism_classification
Cell biology
030104 developmental biology
Gene Expression Regulation
KLF2
lcsh:Q
Dose Fractionation
Radiation
Protein C
Signal Transduction
medicine.drug
Zdroj: Scientific Reports, Vol 10, Iss 1, Pp 1-13 (2020)
Scientific Reports
ISSN: 2045-2322
DOI: 10.1038/s41598-020-64672-3
Popis: Kruppel-like factor 2 (KLF2) is a positive transcriptional regulator of several endothelial protective molecules, including thrombomodulin (TM), a surface receptor, and endothelial nitric oxide synthase (eNOS), an enzyme that generates nitric oxide (NO). Loss of TM and eNOS causes endothelial dysfunction, which results in suppressed generation of activated protein C (APC) by TM-thrombin complex and in upregulation of intercellular adhesion molecule 1 (ICAM-1). Mechanistic studies revealed that activation of extracellular signal-regulated kinase 5 (ERK5) via upregulation of myocyte enhancer factor 2 (MEF2) induces KLF2 expression. Radiation causes endothelial dysfunction, but no study has investigated radiation’s effects on the KLF2 pathway. Because fractionated radiation is routinely used during cancer radiotherapy, we decided to delineate the effects of radiation dose fractionation on the KLF2 signaling cascade at early time points (up to 24 h). We exposed human primary endothelial cells to radiation as a series of fractionated or as a single exposure, with the same total dose delivered to each group. We measured the expression and activity of critical members of the KLF2 pathway at subsequent time points, and determined whether pharmacological upregulation of KLF2 can reverse the radiation effects. Compared to single exposure, fractionated radiation profoundly suppressed KLF2, TM, and eNOS levels, subdued APC generation, declined KLF2 binding ability to TM and eNOS promoters, enhanced ICAM-1 expression, and decreased expression of upstream regulators of KLF2 (ERK5 and MEF2). Pharmacological inhibitors of the mevalonate pathway prevented fractionated-radiation–induced suppression of KLF2, TM, and eNOS expression. Finally, fractionated irradiation to thoracic region more profoundly suppressed KLF2 and enhanced ICAM-1 expression than single exposure in the lung at 24 h. These data clearly indicate that radiation dose fractionation plays a critical role in modulating levels of KLF2, its upstream regulators, and its downstream target molecules in endothelial cells. Our findings will provide important insights for selecting fractionated regimens during radiotherapy and for developing strategies to alleviate radiotherapy-induced toxicity to healthy tissues.
Databáze: OpenAIRE
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