Abstract
Radiotherapy is widely used for cancer treatment. The standard fractionated radiotherapy consists of exposure to 2 Gy of X-ray per day for several weeks and total doses with 50 to 90 Gy. However, recurrence frequently occurs due to tumor radioresistance resulting in the failure of radiotherapy. Therefore, it is important to elucidate the underlying mechanisms of radioresistance for the improvement of radiotherapy.
We have studied DNA damage response to fractionated radiation (FR). Long-term FR exposure to 0.5-Gy X-rays twice per day, for more than 31 days conferred radioresistance on human tumor cell lines, HepG2 and HeLa, along with cyclinD1 overexpression. Radioresistance was due to less induction of apoptosis.
CyclinD1 overexpression was brought by down-regulation of proteolysis via the AKT/GSK3b pathway. To determine the role of AKT-mediated cyclinD1 overexpression in radioresistance, we treated long-term FR cells with an AKT inhibitor, AKT/PKB signaling inhibitor-2 (API-2). API-2 suppressed AKT phosphorylation resulting in down-regulation of cyclinD1 expression. Under this condition, API-2 completely suppressed the radioresistant phenotype of long-term FR cells.
In conclusion, we can control radioresistance in combination in an AKT inhibitor. The present study suggests the importance of the AKT/ cyclinD1 pathway as a novel target to improve the outcome of radiotherapy, especially on recurrent radioresistant tumors
