Low-dose Fractionated Radiation Increases Cisplatin Sensitivity In Ovarian Cancer Via PI3K/AKT/GSK-3? Pathway

Objective Ovarian cancer is the most lethal gynecological malignancy and is the 5th primary cause of mortality from cancer among women in the world.According to statistics,there are more than 20,000 new cases of ovarian cancer each year in the United States,the mortality rate is higher than 30%.Currently,cytoreductive surgery combined with platinum or paclitaxel-based chemotherapy is the first-line treatment for ovarian cancer patients.Although most patients initially respond to the treatment,60-85% of patients may suffer from relapse due to the chemotherapeutic drug resistance on platinum.Eventually,the advanced ovarian cancer patients have a low 5-year survival rate at 25-30%.Therefore,Exploring the molecular mechanisms of the chemotherapy resistance and finding a new method to improve the sensitivity of chemotherapeutic drugs of ovarian cancer is essential.The mechanism of resistance to ovarian cancer is a complex process associated with a variety of factors.Abnormal apoptosis signals can induce the apoptosis of tumor cells,changing the cell sensitivity to chemical drugs.Studies found that Low-dose fractionated radiation(LDFRT)is an enhancer of chemotherapy drug without developing resistance in higher and conventional doses of chemoradiotherapy.But the mechanism is not clear.PI3K/AKT/GSK-3?,as an elementary survival and antiapoptotic signaling pathway,plays a pivotal role in many cellular processes,including survival,proliferation,metastasis,motility and drug-resistance in multiple tumor types.The objective of the report is to evaluate whether the low-dose fractionated radiation(LDFRT)could enhance the sensitivity of the SKOV3/DDP drug-resistant human ovarian cancer cells to cisplatin by inhibiting PI3K/AKT/GSK-3? pathway.Methods The SKOV3/DDP ovarian cancer cells were divided into three groups: control group,LDFRT group and conventional-dose radiation group.All the SKOV3/DDP cells in the three groups were stimulated with different concentrations of cisplatin(0,1.25,2.5,5,10,20 ?g/ml)for 48 h.The cell counting kit 8(CCK8)method was employed for determining the proliferation inhibition rate of the three groups for SKOV3/DDP ovarian cancer cell.Flow cytometry(FCM)was used for detecting apoptosis rate.And then,the protein level of AKT,P-AKT,GSK-3?,P-GSK-3?,P21,Cyclin D1 and P27 were examined by Western blot analysis.Results As we expected,LDFRT significantly reduced half maximal inhibitory concentration(IC50)and promoted apoptosis of SKOV3/DDP cells' response to cisplatin.Moreover,we showed that protein expression of P-AKT,P-GSK-3? and Cyclin D1 was decreased,P21 and P27 were greatly increased in LDFRT group while the level of total AKT and GSK-3? had no significant difference in contrast to that of the control group and conventional-dose radiation group.Conclusion These results suggested Phosphatidylinositol 3 kinase/protein kinase B/glycogen synthase kinase-3?(PI3K/AKT/GSK-3?)pathway is of great importance in cisplatin-resistance of OC.Furthermore,LDFRT could sensitize cisplatin-resistant SKOV3/DDP cells,which may be medicated through inactivation of the PI3K/AKT/GSK-3? pathway.