Cellular oxidative stress response mediates radiosensitivity in Fus1-deficient mice

Area of Science:

• Mitochondrial biology
• Radiation oncology
• Oxidative stress research

Background:

• The mechanism of normal tissue radiosensitivity, crucial for cancer radiotherapy side effects, remains unclear.
• Fus1 (fused in sarcoma) deficiency was previously shown to increase radiosensitivity at multiple levels.
• Fus1-deficient models exhibit elevated oxidative stress, suggesting a role for antioxidant defenses.

Purpose of the Study:

• To investigate the role of dysregulated cellular antioxidant defenses in Fus1-deficient radiosensitivity.
• To evaluate the therapeutic potential of targeting oxidative stress in Fus1-deficient radiosensitive models.

Main Methods:

• Treatment of Fus1 knockout (KO) mice and cultured epithelial cells with pyridoxamine (PM), an antioxidant.
• Assessment of ionizing radiation (IR)-induced damage, survival rates, oxidative stress markers, and DNA repair.
• Evaluation of antioxidant enzyme activities (cytochrome C, Sod 2) and signaling pathways (STAT3).

Main Results:

• PM treatment ameliorated GI epithelial damage and increased survival in irradiated Fus1 KO mice.
• Fus1 KO cells showed enhanced IR-induced oxidative stress due to deficient antioxidant defenses (low cytochrome C, Sod 2, STAT3).
• PM and Sod 2 mimetic Tempol normalized oxidative stress, improving DNA damage response and synthesis in Fus1 KO cells.

Conclusions:

• Dysregulation of antioxidant response and defective redox homeostasis mediate radiosensitivity in Fus1-deficient models.
• Targeting oxidative stress with agents like PM offers a potential strategy to mitigate radiotherapy toxicity in susceptible individuals.