Radiobiology revisited
Despite advances in targeted radiotherapy, ionising radiation causes substantial side effects in normal tissues. Emerging evidence underscores a role for the microvascular endothelium in the cellular response to radiation. At the molecular level, key actors in this response seem to be the p38 MAPK proteins, which become activated after radiation-induced oxidative stress. To map the endothelial response to oxidative stress induced by ionising radiation, the EU-funded P38RADOX (Identification of p38 MAPK partners in the response of endothelium to oxidative stress and ionizing radiation. Impact in cancer radiotherapy) project set out to identify new signalling molecules implicated in the p38 MAPK pathway. Using a combination of proteomic, biochemical and microscopic methodologies, researchers identified nucleophosmin (NPM) as a new cytosolic partner of p38 MAPK in endothelial cells. They observed that oxidative stress and ionising radiation induced the dephosphorylation of NPM, causing it to translocate to the nucleus as well as affecting the DNA damage response. In particular, it delayed the repair of DNA double strand breaks and led to an accumulation of DNA errors in these cells. Collectively, the study findings indicate a role for NPM in endothelial genomic instability, by impairing detection of DNA damage and delaying cellular DNA repair. Although validation of this data in clinical samples is pending, it could initiate further cellular dysfunction and could lead to important vascular pathologies. NPM could thus serve as a target for reducing endothelial dysfunction and toxicity associated with radiotherapy treatments to improve radiotherapy outcome.
