Dysregulated expression of cell surface glycoprotein CDCP1 in prostate cancer.
CUB-domain-containing protein 1 (CDCP1) is a trans-membrane protein regulator of cell adhesion with a potent pro-migratory function in tumors. Given that proteolytic cleavage of the ectodomain correlates with outside-in oncogenic signaling, we characterized glycosylation in the context of cellular processing and expression of CDCP1 in prostate cancer. We detected 135 kDa full-length and proteolytic processed 70 kDa species in a panel of PCa cell models. The relative expression of full-length CDCP1 correlated with the metastatic potential of syngeneic cell models and an increase in surface membrane expression of CDCP1 was observed in tumor compared to adjacent normal prostate tissues. We demonstrated that glycosylation of CDCP1 is a prerequisite for protein stability and plasma membrane localization, and that the expression level and extent of N-glycosylation of CDCP1 correlated with metastatic status. Interestingly, complex N-linked glycans with sialic acid chains were restricted to the N-terminal half of the ectodomain and absent in the truncated species. Characterization of the extracellular expression of CDCP1 identified novel circulating forms and revealed that extracellular vesicles provide additional processing pathways. Employing immunoaffinity mass spectrometry, we detected elevated levels of circulating CDCP1 in patient urine with high-risk disease. Our results establish that differential glycosylation, cell surface presentation and extracellular expression of CDCP1 are hallmarks of PCa progression.
Leroy T. Canoles Jr. Cancer Research Center, Eastern Virginia Medical School, Norfolk, VA, USA.|Department of Microbiology & Molecular Cell Biology, Eastern Virginia Medical School, Norfolk, VA, USA.
Lifang
L
Yang
Leroy T. Canoles Jr. Cancer Research Center, Eastern Virginia Medical School, Norfolk, VA, USA.
Sucharita M
SM
Dutta
Leroy T. Canoles Jr. Cancer Research Center, Eastern Virginia Medical School, Norfolk, VA, USA.|Department of Pathology and Anatomy, Eastern Virginia Medical School, Norfolk, VA, USA.
Dean A
DA
Troyer
Urology of Virginia, Norfolk, VA, USA.
Jefferson B
JB
Lin
Leroy T. Canoles Jr. Cancer Research Center, Eastern Virginia Medical School, Norfolk, VA, USA.|Urology of Virginia, Norfolk, VA, USA.
Raymond A
RA
Lance
Leroy T. Canoles Jr. Cancer Research Center, Eastern Virginia Medical School, Norfolk, VA, USA.|Department of Microbiology & Molecular Cell Biology, Eastern Virginia Medical School, Norfolk, VA, USA.
Julius O
JO
Nyalwidhe
Department of Cell and Molecular Pharmacology and Experimental Therapeutics, Medical University of South Carolina, Charleston, SC, USA.
Richard R
RR
Drake
Leroy T. Canoles Jr. Cancer Research Center, Eastern Virginia Medical School, Norfolk, VA, USA.|Department of Microbiology & Molecular Cell Biology, Eastern Virginia Medical School, Norfolk, VA, USA.|Department of Pathology and Anatomy, Eastern Virginia Medical School, Norfolk, VA, USA.
O John
OJ
Semmes
D015703:Antigens, CD / Q000378:metabolism*; D000951:Antigens, Neoplasm; D015815:Cell Adhesion Molecules / Q000378:metabolism*; D045744:Cell Line, Tumor; D018450:Disease Progression; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D006031:Glycosylation; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D008297:Male; D013058:Mass Spectrometry; D009363:Neoplasm Proteins / Q000378:metabolism*; D011471:Prostatic Neoplasms / Q000378:metabolism / Q000473:pathology*; D046888:Tissue Array Analysis
D015703:Antigens, CD; D000951:Antigens, Neoplasm; C432044:CDCP1 protein, human; D015815:Cell Adhesion Molecules; D009363:Neoplasm Proteins
CUB-domain containing protein 1; biomarker; glycoprotein; prostate cancer