Abstract
Radiotherapy has been the most effective nonsurgical treatment for cancer. However, the recurrence is frequently occurred by the acquisition of radioresistance of tumors and resulting failures of clinical outcome. Therefore, the determination of underlying mechanism of the radioresistance of tumor cells may provide novel therapeutic approaches to eradicate radioresistant cells.
This study is the first to demonstrate that long-term fractionated radiation (FR) for more than 31 days conferred radioresistance of tumor cells with cyclinD1 overexpression. The time course analyses revealed that the level of cyclinD1 was unchanged until day 14, but was significantly elevated on day 31. The radioresistance was stably maintained in the tumor cells even on 31 days after the cessation of irradiation.
CyclinD1 overexpression was brought about by a feedback loop mediated by DNA-PK/AKT/GSK3b-mediated down-regulation of cyclinD1 proteorysis. CyclinD1 overexpression produced DSBs in S-phase which again activated DNA-PK, compleating the loop. Inhibition of the AKT/GSK-3b/cyclinD1 pathway by treating HepG2 and HeLa cells either with an AKT inhibitor or siRNA targeting cyclinD1 suppressed the radioresistance of long-term FR cells.
Present observations give a mechanistic insight for acquired radioresistance of tumor cells through long-term FR exposures, and provide novel therapeutic targets to radiosensitize recurrent radioresistant cells.
