DNA damage responses are the basis for conventional cancer treatments like ã-irradiation and chemotherapy, and the p53 protein is a key mediator in this process. Our lab has recently demonstrated that elevation of intracellular cAMP also leads to inhibition of DNA damage-induced apoptosis, and results so far have shown that this inhibition is mediated by downregulation of p53 at the level of protein stabilisation (Hallan Naderi et al., manuscript in preparation).
Epstein-Barr virus is a DNA tumour virus implicated in the development of mononucleosis and cancers like Burkitt’s lymphoma, Hodgkin's lymphoma, gastric cancer, and nasopharyngeal carcinoma. We have recently shown in our lab that EBV-infection of B-cells inhibits the antiproliferative effect of cAMP (Kloster et al., manuscript in preparation).
The aims of the present project were to unravel whether EBV-infection of B-cells prevents cAMP-mediated inhibition of DNA damage-induced apoptosis triggered by ã-radiation, and if so, to establish the mechanisms involved. Our experiments showed that EBV-transformed B-cells were more resistant to ã-radiation, and that EBV-infection indeed prevents cAMP-mediated inhibition of apoptosis induced by ionizing radiation. Thus, we revealed that the stability of p53 in EBV-infected B cells was largely unaffected by cAMP, whereas the stability of p53 in control cells was reduced. Our analysis of the mechanisms involved in the ability of EBV to prevent cAMP-mediated destabilization of p53 revealed that activation of Chk1 and Chk2 were unaffected, suggesting that the inhibitory effect of EBV on cAMP-mediated regulation of DNA damage-induced apoptosis is not mediated via checkpoint-control upstream of p53, but rather that the cAMP-mediated pathway as such is affected.