Abstract
Carboxyl-ester lipase (CEL) is a pancreatic fat-digesting enzyme associated with human disease. Rare mutations in the CEL gene cause a syndrome of pancreatic exocrine and endocrine dysfunction denoted MODY8, whereas a recombined CEL allele increases the risk for chronic pancreatitis. Moreover, CEL has been linked to pancreatic ductal adenocarcinoma (PDAC) through a postulated oncofetal CEL variant termed feto-acinar pancreatic protein (FAPP). The monoclonal antibody mAb16D10 was previously reported to detect a glycotope in the highly O-glycosylated, mucin-like C terminus of CEL/FAPP. We here assessed the expression of human CEL in malignant pancreatic lesions and cell lines. CEL was not detectably expressed in neoplastic cells, implying that FAPP is unlikely to be a glycoisoform of CEL in pancreatic cancer. Testing of the mAb16D10 antibody in glycan microarrays then demonstrated that it recognized structures containing terminal GalNAc-α1,3(Fuc-α1,2)Gal (blood group A antigen) and also repeated protein sequences containing GalNAc residues linked to Ser/Thr (Tn antigen), findings that were supported by immunostainings of human pancreatic tissue. To examine whether the CEL glycoprotein might be modified by blood group antigens, we used high-sensitivity MALDI-TOF MS to characterize the released O-glycan pool of CEL immunoprecipitated from human pancreatic juice. We found that the O-glycome of CEL consisted mainly of core 1/core 2 structures with a composition depending on the subject's FUT2 and ABO gene polymorphisms. Thus, among digestive enzymes secreted by the pancreas, CEL is a glycoprotein with some unique characteristics, supporting the view that it could serve additional biological functions to its cholesteryl esterase activity in the duodenum.
Highlights
Neither the Carboxyl-ester lipase (CEL)-HYB variant nor specific CEL variable number of tandem repeats (VNTR) lengths were enriched among pancreatic cancer cases compared with controls [8, 35]
The identification and characterization of feto-acinar pancreatic protein (FAPP), a postulated oncofetal variant of CEL with six VNTR repeats, has raised the possibility that glycoisoforms of CEL could serve as diagnostic markers or even targets for treatment in pancreatic cancer [27,28,29, 36]
By using complementary techniques, we found that CEL was not detectably expressed in either neoplastic cells of pancreatic ductal adenocarcinoma (PDAC) tissue sections or in the pancreatic cancer cell lines examined
Summary
The mucinous domain of pancreatic carboxyl-ester lipase (CEL) contains core 1/core 2 O-glycans that can be modified by ABO blood group determinants. The monoclonal antibody mAb16D10 was previously reported to detect a glycotope in the highly O-glycosylated, mucin-like C terminus of CEL/FAPP. Rare mutational events affecting the VNTR region cause an inherited syndrome of diabetes and pancreatic exocrine dysfunction (MODY8) [10], most likely because of protein aggregation and endoplasmic reticulum stress resulting. The antibody showed a high affinity for blood group A antigens, which led to the finding that ABO blood group determinants are present on the C terminus of CEL
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