Novel pathways involved in cisplatin resistance identified by a proteomics approach in non‐small‐cell lung cancer cells

Abstract

Although platinum‐based chemotherapy remains the standard‐of‐care for most patients with advanced non‐small‐cell lung cancer (NSCLC), acquired resistance occurs frequently predicting poor prognosis. To examine the mechanisms underlying platinum resistance, we have generated and characterized by proteomic approach the resistant A549 CDDP‐resistant (CPr‐A549) and their parental A549 cells, identifying 15 proteins differentially expressed (13 upregulated and 2 downregulated in CPr‐A549). In details, we highlighted a coherent network of proteins clustering together and involved in altered protein folding and endoplasmic reticulum stress, correlated with epithelial to mesenchymal transition process and cancer stem cell markers, where vimentin played a hierarchical role, ultimately resulting in increased aggressive features. By using publicly available databases we showed that the modulated proteins could contribute to NSCLC carcinogenesis and correlate with NSCLC patients prognosis and survival probability, suggesting that they can be used as novel potential prognostic/predictive biomarkers or therapeutic targets to overcome platinum‐resistance.

HSP90 identified by a proteomic approach as druggable target to reverse platinum resistance in ovarian cancer

“…Interestingly a data-mining meta-analyses integrating the results from multiple siRNA screening in EOC also identify HSP90 as a central hub and an effective therapeutic target [34]. Notably, we have also discovered HSP90 as a critical hub within a network of differentially expressed proteins identified in a Pt-res NSCLC isogenic model [10], supporting the possibility that the same mechanism is present in different tumor types. Indeed preliminary results showed also in this Pt-res NSCLC model a synergistic antitumor interaction between HSP90i and CDDP 1 .…”

“…Proteomic experiments were performed as described by Milone et al . [9]. In detail, four independent biological conditions are required to give statistic confidence to 2‐D DIGE data.…”

“…Protein extracts were separated on preparative gels and recovered from the gels for identification by LC‐MS/MS as previously described [9]. Mass fingerprinting searching was carried out in Swiss‐Prot/TrEMBL database using Mascot (Matrix Science Ltd., London, UK).…”

“…Protein extraction after 48 h of cell culture and immunoblotting was performed as previously described [9]. Western blots were quantified using imagej software (Rasband, W.S., U.S., National Institutes of Health, Bethesda, Maryland, USA).…”

Proteomic Technology “Lens” for Epithelial-Mesenchymal Transition Process Identification in Oncology

“…These proteins are involved in misfolding of proteins, endoplasmic reticulum stress, positively correlated with EMT and CSC markers. These proteins could be further developed in NSCLC patient prognosis and survival markers [122].…”