Sensitization of human melanoma cells for TRAIL-induced apoptosis by a selective aurora kinase A inhibitor

Different therapeutic strategies in metastatic melanoma focused on signalling pathways controlling cell proliferation, cell cycle and apoptosis. While TRAIL (TNF-related apoptosis inducing ligand) has been shown to be an interesting candidate for inducing apoptosis in cancer cells without affecting normal cells, the ability of cancer cells to develop resistance, limits its therapeutic potential. Using a recently established experimental A-375 melanoma cell model for investigating TRAIL resistance, we could demonstrate that the aurora kinase A inhibitor Alisertib (MLN 8237) enhances the proapoptotic effects of TRAIL and sensitizes TRAIL-selected melanoma cells with acquired resistance, associated with an activation of intrinsic mitochondrial apoptotic pathways. In course of this activation an upregulation of p53 in the nuclear fraction was shown. Thus, the aurora kinase A inhibitor Alisertib is able to overcome TRAIL-induced resistance in melanoma cells suggesting the combination of TRAIL and Alisertib as a promising therapeutic strategy for metastatic melanoma.