New Insights into Neuroblastoma Cisplatin Resistance: A Comparative Proteomic and Meta-Mining Investigation

Neuroblastoma is one of the most aggressive solid tumors in the childhood. Therapy resistance to anticancer drugs represents the major limitation to the effectiveness of clinical treatment. To better understand the mechanisms underlying cisplatin resistance, we performed a comparative proteomic study of the human neuroblastoma cell line SH-SY5Y and its cisplatin resistant counterpart by both the classical 2-DE electrophoresis coupled to mass spectrometry and the more innovative label-free nLC-MS(E). The differentially expressed proteins were classified by bioinformatic tools according to their biological functions and their involvement in several cellular processes. Moreover, a meta-mining investigation of protein ontologies was also performed on available data from previously published proteomics studies to highlight the modulation of significant cellular pathways, which may regulate the sensitivity of neuroblastoma to cisplatin. In particular, we hypothesized a major role of the transcription factor nuclear factor-erythroid 2-related factor 2 (Nrf2) pathway. Confocal microscopy experiments, enzyme assay, and Western blotting of proteins regulated by Nrf2 provided evidences that this pathway, playing a protective role in normal cells, may represent a potential novel target to control cisplatin resistance in neuroblastoma.