Abstract

Cisplatin is widely used for the treatment of solid tumours including small cell lung cancers, but its success is often compromised by relapse and resistance to further treatment. Extracellular signal-regulated kinase 1/2 (ERK1/2) and Akt are two major cell survival pathways that are upregulated and activated in lung cancer tissues. Phosphorylated ERK1/2 (p-ERK1/2) and Akt (p-Akt) can be further stimulated by chemotherapeutics in cancer cells. Although individually targeting the ERK1/2 or Akt pathway has been reported to sensitize cancer cells to therapy, the effect of concurrently blocking these two pathways on the sensitivity of lung cancer cells to cisplatin has not been investigated. In the present study, we aimed to determine whether the ERK1/2 and Akt pathways contribute to cisplatin resistance in human small cell lung cancer A549 cells. The results showed that cisplatin activates p-ERK1/2 and p-Akt in A549 cells. Blockade of either of these pathways with chemical inhibitors moderately sensitized A549 cells to cisplatin-induced apoptosis and reduced cell viability. Strikingly, concurrent inhibition of p-ERK1/2 and p-Akt significantly potentiated cisplatin cytotoxicity in vitro and in vivo. The sensitization of A549 cells to cisplatin cytotoxicity induced by p-Akt inhibition was mediated by the upregulation of PUMA, whereas that induced by p-ERK1/2 inhibition occurred by Bcl-2 downregulation. These data indicate that the cooperative effects of p-ERK1/2 and p-Akt on attenuating cisplatin cytotoxicity are mediated by PUMA and Bcl-2 regulation, and concurrently blocking these pathways may be an effective strategy for improving the efficacy of cisplatin as anticancer treatment.