Label-free global serum proteomic profiling reveals novel celecoxib-modulated proteins in familial adenomatous polyposis patients.
Celecoxib, a selective inhibitor of cyclooxygenase-2 (Cox-2), was efficacious in clinical prevention trials of patients with familial adenomatous polyposis (FAP) and sporadic colorectal cancer. To identify as yet poorly defined molecular determinants of celecoxib efficacy, a multidimensional serum fractionation approach was used coupled with nanospray tandem mass spectrometry to perform label-free global proteomic profiling of serum samples from the FAP/celecoxib prevention trial. Subsequently, the application of an algorithm for large-scale biomarker discovery on comparative serum proteomic profiles of pre- and post-celecoxib treatment samples identified 83 potentially celecoxib-responsive proteins from various cellular compartments, biological processes and molecular functions. Celecoxib modulation of some of these proteins was confirmed in serum samples of FAP patients and colorectal cancer cell lines by Western blotting. Thus, using a shotgun procedure to rapidly identify important celecoxib-modulated proteins, this pilot study has uncovered novel systemic changes some of which are highly relevant for carcinogenesis and vascular biology. Validation of selected markers, especially those involved in key signaling networks and those considered molecular indicators of cardiovascular pathology, in larger celecoxib clinical trials is expected to provide insights into the molecular mechanisms of celecoxib and the efficacy/toxicity issues related to its use as a chemopreventive agent.
Fatima
Naheed
N
Molecular Oncology Program, Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of Karachi, Karachi - 7520, Pakistan.
Chelius
Dirk
D
Luke
Brian T
BT
Yi
Ming
M
Zhang
Terry
T
Stauffer
Stacey
S
Stephens
Robert
R
Lynch
Patrick
P
Miller
Ken
K
Guszczynski
Tad
T
Boring
Daniel
D
Greenwald
Peter
P
Ali
Iqbal Unnisa
IU
D011125:Adenomatous Polyposis Coli / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D001798:Blood Proteins / Q000378:metabolism*; D015153:Blotting, Western; D000068579:Celecoxib; D002853:Chromatography, Liquid; D019295:Computational Biology; D006801:Humans; D010446:Peptide Fragments; D040901:Proteomics; D011720:Pyrazoles / Q000494:pharmacology*; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D013449:Sulfonamides / Q000494:pharmacology*
D000894:Anti-Inflammatory Agents, Non-Steroidal; D001798:Blood Proteins; D010446:Peptide Fragments; D011720:Pyrazoles; D013449:Sulfonamides; D000068579:Celecoxib