Radiation induced signaling in mammalian cells

Abstract

Ionising radiation leads to a cascade of signaling events which include activation of alarm signals, cytotoxic and cytoprotective signaling pathways, nitric oxide production etc. These events culminate in the death or survival of the irradiated cell. The end result seems to depend upon the pathway predominantly activated. Ionizing radiation has been an important part of cancer treatment for almost a century; radiotherapy is given as fractionated doses ranging from 2-4 Gy, per fraction. The effect of fractionated doses of and#947; irradiation (2Gy per fraction over 5 days), as delivered in cancer radiotherapy, was compared with acute doses of 10 and 2Gy, in A549 cells. A549 cells were found to be relatively more radioresistant if the 10Gy dose was delivered as a fractionated regimen. There was intense activation of DNA repair pathway associated genes (DNA-PK, ATM, Rad52, MLH1 and BRCA1), efficient DNA repair and phospho-p53 was found to be translocated to the nucleus of A549 cells exposed to fractionated irradiation. MCF-7 cells responded differently in fractionated regimen. Silencing of the Rad52 gene in fractionated group of A549 cells made the cells radiosensitive. The above result indicated increased radioresistance in A549 cells due to the activation of Rad52 gene. Having established that among the different cell lines, A549 was the most adioresistant, the variance in signaling pattern and effectiveness of cell killing with the change in LET was looked at. The survival of the A549 cell line could also be significantly decreased by charged particle irradiation. The mechanism of which seems to be a lack of repair, despite the activation of some of the component of the repair pathway. Having established that the response of the signaling factors varied with dose, dose fractionation, time, microenvironment and radiation quality (LET), it was of interest to investigate radiation induced bystander signaling. The contribution of the bystander effect to the decrease in survival of A549 cells cannot be ruled out.