FOXO3a mediates the cytotoxic effects of cisplatin in lung cancer cells.

Cisplatin is one of the major chemotherapeutic agents used against different human cancers. A better understanding of the downstream cellular targets of cisplatin will provide information on its mechanism of action. FOXO3a is a member of the FOXO transcription factor family, which modulates the expression of genes involved in cell cycle arrest, apoptosis, and other cellular processes. In this study, we have investigated the effects of cisplatin in a panel of lung cancer cell lines. The results showed that cisplatin inhibited the proliferation of these lung cancer cell lines by inhibiting the PI3K/AKT pathway, with evidence of decreasing phosphorylation of PI3K and AKT under cisplatin treatment, and constitutively activating AKT1 could reduce cisplatin-induced cell apoptosis. More importantly, cisplatin significantly inhibited FOXO3a phosphorylation (at Thr32, AKT phosphorylation site) and induced FOXO3a nuclear accumulation, which in turn increased the expression of FOXO3a-dependent apoptotic protein Bim. Knockdown of FOXO3a expression using small interfering RNA attenuated cisplatin-induced apoptosis. Furthermore, activation of FOXO3a induced cell apoptosis irrespective of p53 status, whereas p53 may act as FOXO3a downstream molecules involved in cisplatin-induced cell apoptosis. Together, our findings suggested that FOXO3a is a relevant mediator of the cytotoxic effects of cisplatin in lung cancer cells.