Abstract
Radiotherapy is generally delivered by cumulative fractionated radiation of 2-Gy X-rays. Radioresistance of tumor cells is closely associated with recurrence and failure after radiotherapy. We have recently revealed that tumor cells acquire radioresistance by AKT/GSK3b-mediated cyclin D1 overexpression induced by long-term fractionated radiation (FR). We expected that tumor radioresistance can be suppressed by targeting AKT/GSK3b/Cyclin D1 pathway.
In this study, we examined the role of AKT signaling in radioresistance against fractionated radiotherapy. Treatment with an AKT inhibitor, AKT/PKB signaling inhibitor-2 (API-2) resulted in down-regulation of cyclin D1 expression in cells with acquired radioresistance. Apoptosis was significantly induced by the combination of radiation and API-2. Furthermore, tumor radioresistance completely was disappeared by API-2 treatment in vitro and in vivo. Also inhibition of the kinase activity of cyclin D1/Cdk4 by a Cdk4 inhibitor was sufficient to abolish radioresistance.
In conclusion, targeting AKT/GSK3b/cyclinD1/Cdk4 pathway would provide a novel treatment approach to improve fractionated radiotherapy and would have an impact on tumor eradication in combination with chemotherapy.
