Abstract
Chemoresistance is a common mode of therapy failure for many cancers. Tumours develop resistance to chemotherapeutics through a variety of mechanisms, with proteins serving pivotal roles. Changes in protein conformations and interactions affect the cellular response to environmental conditions contributing to the development of new phenotypes. The ability to understand how protein interaction networks adapt to yield new function or alter phenotype is limited by the inability to determine structural and protein interaction changes on a proteomic scale. Here, chemical crosslinking and mass spectrometry were employed to quantify changes in protein structures and interactions in multidrug-resistant human carcinoma cells. Quantitative analysis of the largest crosslinking-derived, protein interaction network comprising 1,391 crosslinked peptides allows for ‘edgotype' analysis in a cell model of chemoresistance. We detect consistent changes to protein interactions and structures, including those involving cytokeratins, topoisomerase-2-alpha, and post-translationally modified histones, which correlate with a chemoresistant phenotype.
Highlights
Chemoresistance is a common mode of therapy failure for many cancers
Modern largescale measurements based on genomics and proteomics technologies have significantly increased the ability to identify novel genes and signalling networks that are involved in the responsiveness of tumours to particular chemotherapeutic agents
Irinotecan is converted by carboxylesterases into the active form SN-38, which exerts its cytotoxic activity through inhibition of topoisomerase 1 (TOP1) religation activity and indirectly results in DNA double strand breaks (DSBs)[4]
Summary
Chemoresistance is a common mode of therapy failure for many cancers. Tumours develop resistance to chemotherapeutics through a variety of mechanisms, with proteins serving pivotal roles. Chemical crosslinking and mass spectrometry were employed to quantify changes in protein structures and interactions in multidrug-resistant human carcinoma cells. Previous efforts have demonstrated the utility of protein interaction reporter (PIR)-crosslinking technology to construct interactome network maps in complex biological systems such as intact virions[18], Escherichia coli[19,20] and human cells[21]. The edges in these networks represent proximal amino acid residues containing both individual protein conformational information for intra-protein linkages, as well as protein interaction and protein complex structural information for inter-protein linkages. Quantification of crosslinked peptides enables measurement of an edgotype map[14] in which protein conformational changes and interaction level changes can be observed between biological phenotypes on a large scale
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