A systems biology approach to the study of cisplatin drug resistance in ovarian cancers.
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.
Chen
Jake Y
JY
Indiana University School of Informatics, Department of Computer and Information Science, Purdue University School of Science, Indianapolis, IN 46202, USA. jakechen@iupui.edu
Yan
Zhong
Z
Shen
Changyu
C
Fitzpatrick
Dawn P G
DP
Wang
Mu
M
D000970:Antineoplastic Agents / Q000008:administration & dosage; D002945:Cisplatin / Q000008:administration & dosage*; D019008:Drug Resistance, Neoplasm / Q000502:physiology; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods*; D006801:Humans; D009363:Neoplasm Proteins / Q000378:metabolism*; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000378:metabolism*; D025941:Protein Interaction Mapping / Q000379:methods; D015398:Signal Transduction / Q000187:drug effects*; D049490:Systems Biology / Q000379:methods*
D000970:Antineoplastic Agents; D009363:Neoplasm Proteins; D002945:Cisplatin