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Published on: December 9, 2015
Quantitative interactome analysis reveals a chemoresistant edgotype
Juan D Chavez1, Devin K Schweppe1, Jimmy K Eng1
1Department of Genome Sciences, University of Washington, Seattle, Washington 98195, USA.
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.
Insights
Understanding how cancer cells develop chemoresistance is crucial. This study used chemical crosslinking and mass spectrometry to analyze protein changes, revealing key alterations in protein interactions and structures linked to drug resistance in carcinoma cells.
Area of Science:
- Biochemistry
- Molecular Biology
- Proteomics
Background:
- Chemoresistance is a primary cause of cancer therapy failure.
- Proteins play critical roles in cancer cells developing resistance to chemotherapeutics.
- Understanding protein structural and interaction changes is key to overcoming chemoresistance.
Purpose of the Study:
- To investigate protein structural and interaction network changes in multidrug-resistant human carcinoma cells.
- To apply chemical crosslinking and mass spectrometry for proteomic-scale analysis of chemoresistance.
Main Methods:
- Utilized chemical crosslinking and mass spectrometry (MS) to analyze protein structure and interactions.
- Quantified changes in a large protein interaction network derived from crosslinking data (1,391 crosslinked peptides).
- Performed 'edgotype' analysis on the protein interaction network in a chemoresistance cell model.
Main Results:
- Detected consistent alterations in protein interactions and structures correlating with a chemoresistant phenotype.
- Identified specific proteins with altered structures and interactions, including cytokeratins, topoisomerase-2-alpha, and modified histones.
- Established a link between proteomic network changes and the development of multidrug resistance.
Conclusions:
- Chemical crosslinking and MS provide a powerful tool to study protein network adaptations in cancer.
- Specific protein interaction and structural changes are associated with chemoresistance.
- This approach offers insights into mechanisms of therapy failure and potential therapeutic targets.
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