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 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.