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Low sensitivity to chemotherapy has been a major challenge in the treatment of non-small-cell lung cancer(NSCLC).It is of great clinical significance to discover its mechanisms to improve cell sensitivity to chemotherapeutic drugs.The forkhead box subfamily O(FOXO)transcriptional factors are downstream factors of the phosphatidylinositol 3-kinase/protein kinase B(PI3K/AKT)pathway and are reported to play pro-apoptotic roles in a variety of cells including NSCLC cells.But their roles and mechanisms in mediating cell response to chemotherapy remain to be discov-ered.We proposed that FOX01 and FOX03a may increase the sensitivity of NSCLC cells to cisplatin.Moreover,we presumed that LY294002,an inhibitor of the PI3K/AKT pathway,may enhance the cytotoxic effects of cisplatin through upregulating FOXO1 and FOXO3a.In the present study,we found that cisplatin initially increased the expressions and nuclear accumulation of FOXO1 and FOXO3a in NSCLC.Knockdown of FOXO1 and FOXO3a significantly decreased the cell sensitivity to cisplatin in vitro and in vivo.Moreover,inhibition of FOXO1 and FOXO3a attenuated cisplatin-induced cell apoptosis independent of Bim,a pro-apoptotic protein downstream of the FOXOs.Moreover,LY294002 synergistically increased the cytotoxic effects of cisplatin.Mechanistically,LY294002 increased the expressions and nuclear accumulation of FOXO1 and FOXO3a.Knockdown of FOXO1 and FOXO3a abrogated the enhancing effect of LY294002 on cisplatin.Taken together,our results suggested that FOXO1 and FOXO3a sensitize NSCLC cells to cisplatin and mediate the enhancina affects of LY294002 on cisnlatin.