A Systems Biology Approach to the Study of Cisplatin Drug Resistance in Ovarian Cancers

Abstract

Cisplatin-induced drug resistance is known to involve a complex set of cellular changes whose molecular mechanism details remain unclear. In this study, we developed a systems biology approach to examine proteomics- and network-level changes between cisplatin-resistant and cisplatin-sensitive cell lines. This approach involves experimental investigation of differential proteomics profiles and computational study of activated enriched proteins, protein interactions, and protein interaction networks. Our experimental platform is based on a Label-free liquid Chromatography/mass spectrometry proteomics platform. Our computational methods start with an initial list of 119 differentially expressed proteins. We expanded these proteins into a cisplatin-resistant activated sub-network using a database of human protein-protein interactions. An examination of network topology features revealed the activated responses in the network are closely coupled. By examining sub-network proteins using gene ontology categories, we found significant enrichment of proton-transporting ATPase and ATP synthase complexes activities in cisplatin-resistant cells in the form of cooperative down-regulations. Using two-dimensional visualization matrixes, we further found significant cascading of endogenous, abiotic, and stress-related signals. Using a visual representation of activated protein categorical sub-networks, we showed that molecular regulation of cell differentiation and development caused by responses to proteome-wide stress as a key signature to the acquired drug resistance.

RETRACTED: Sensitization of squamous cell carcinoma to cisplatin induced killing by natural agents

“…As chemotherapy is becoming an important part of the treatment, resistance to cisplatin is also becoming a frequent mechanism of treatment failure. Cisplatin-induced drug resistance is known to involve a complex set of cellular changes whose exact molecular mechanism remains elusive [15]. Decreased intracellular concentration due to decreased drug uptake, increased reflux or increased inactivation by sulfhydryl molecules such as glutathione, increased excision of the adducts from DNA by repair pathways, increased lesion bypass and altered expression of regulatory proteins involved in signal transduction pathways that control the apoptotic pathway can cause resistance to cisplatin [16].…”

Pathway and network analysis in proteomics

“…A functional category crosstalk network was constructed based on protein interaction networks for ovarian cancer drug resistance study in 2007. This network was first shown as a matrix of interactions between related GO terms, also called GO-GO interactions [78], which took the advantages of both local topological information and group functional information. Another way to simplify complex network visualization is to use the concept of molecular network terrain.…”

Unraveling Human Complexity and Disease With Systems Biology and Personalized Medicine

“…Figure 1B shows a visualization of a gene functional category crosstalk network, using proteomics data derived from an ovarian cancer drug-resistance cell line study compared with ovarian cancer drug-sensitive cell line [53]. Different from networks at the more detailed molecular interaction level, gene functional category crosstalk networks represent integrative biology views at a higher level.…”