Radiotherapy is an effective treatment for
lung cancer but lacks a reliable prediction method.
Cell-free nucleic acids in plasma have been reported as a novel
tumor marker. Here, we evaluate circulating
succinate dehydrogenase 5 (SDH5)
mRNA in plasma and SDH5
protein in
tumors, assess their predictive value in
lung cancer patients undergoing
radiotherapy, and explore the underlying mechanisms. Methods: SDH5 expression was measured in peripheral blood samples and fresh
tumor specimens from 208
non-small cell lung cancer (NSCLC) patients and correlated with clinical outcomes. SDH5 knockout mice and human xenograft mice were used to evaluate radiosensitivity. Cell growth, apoptosis, and the DNA damage response were assessed. Relevant
RNA and
protein levels were analyzed by qRT-PCR and Western blotting. Immunoprecipitation and GST pulldown assays were performed to detect
protein-
protein interactions. Polyubiquitination of p53 was examined by an in vitro ubiquitination assay. Results: Plasma and
tumor SDH5
mRNA levels were positively correlated (rho=0.894, P<0.001). Patients with relatively low SDH5 levels in plasma (0.47, 0.12-0.89) and
tumors (3.85, 0.96-7.23) had a better prognosis after
radiotherapy (median PFS: 30.0 versus 15.0 months, hazard ratio: 0.276, 95% CI: 0.201-0.379, P<0.001). In SDH5 knockout mice, the lung epithelial cells exhibited increased DNA damage after radiation. In human lung xenograft mice, SDH5-deficient
tumors had a smaller volume after
radiotherapy. Furthermore, SDH5 depletion inhibits p53 degradation via the
ubiquitin/
proteasome pathway, which promotes apoptosis and enhances radiosensitivity in NSCLC. Conclusion: Our findings provide a novel noninvasive method for prediction of response to
radiotherapy and may have significant implications for
cancer radiotherapy.