Protein Folding Stability Profiling of Colorectal Cancer Chemoresistance Identifies Functionally Relevant Biomarkers

Reported here is the application of three protein folding stability profiling techniques (including the stability of proteins from rates of oxidation, thermal protein profiling, and limited proteolysis approaches) to identify differentially stabilized proteins in six patient-derived colorectal cance...

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Bibliographic Details
Published in:Journal of proteome research 2023-06, Vol.22 (6), p.1923-1935
Main Authors: Quan, Baiyi, Bailey, Morgan A., Mantyh, John, Hsu, David S., Fitzgerald, Michael C.
Format: Article
Language:English
Subjects:
Animals
Biomarkers
Cell Line, Tumor
Colorectal Neoplasms - drug therapy
Colorectal Neoplasms - genetics
Colorectal Neoplasms - metabolism
Disease Models, Animal
Drug Resistance, Neoplasm - genetics
Humans
Oxaliplatin - pharmacology
Oxaliplatin - therapeutic use
Protein Folding
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Summary:Reported here is the application of three protein folding stability profiling techniques (including the stability of proteins from rates of oxidation, thermal protein profiling, and limited proteolysis approaches) to identify differentially stabilized proteins in six patient-derived colorectal cancer (CRC) cell lines with different oxaliplatin sensitivities and eight CRC patient-derived xenografts (PDXs) derived from two of the patient derived cell lines with different oxaliplatin sensitivities. Compared to conventional protein expression level analyses, which were also performed here, the stability profiling techniques identified both unique and novel proteins and cellular components that differentiated the sensitive and resistant samples including 36 proteins that were differentially stabilized in at least two techniques in both the cell line and PDX studies of oxaliplatin resistance. These 36 differentially stabilized proteins included 10 proteins previously connected to cancer chemoresistance. Two differentially stabilized proteins, fatty acid synthase and elongation factor 2, were functionally validated in vitro and found to be druggable protein targets with biological functions that can be modulated to improve the efficacy of CRC chemotherapy. These results add to our understanding of CRC oxaliplatin resistance, suggest biomarker candidates for predicting oxaliplatin sensitivity in CRC, and inform new strategies for overcoming chemoresistance in CRC.
ISSN:1535-3893
1535-3907
DOI:10.1021/acs.jproteome.3c00045