Mucin Glycosylation Is Altered by Pro-Inflammatory Signaling in Pancreatic-Cancer Cells

Abstract

Altered glycosylation on the surfaces or secreted proteins of tumor cells is common in pancreatic cancer and is thought to promote cancer progression, but the factors leading to the changes in carbohydrate structures are incompletely understood. We hypothesized that pro-inflammatory conditions can lead to alterations in cancer-associated glycans on mucins produced by pancreatic-cancer cells. Using a novel antibody-glycan microarray method, we measured the effects of pro-inflammatory stimuli (oxidative stress and treatment with the cytokines IFNγ, IL-1α, and TNFα) on the expression and glycosylation of the mucins MUC1, MUC5AC, and MUC16 in multiple pancreatic cancer cell lines. Mucin glycosylation was significantly affected in specific cell lines, particularly in structures involving terminal galactose or N-acetylgalactosamine. In addition, the responses of the cell lines grouped according to the expression of cell-surface markers that are associated with tumorigenicity, as cell lines bearing minimal surface markers showed evidence of increased O-glycan extension and decreased presentation of terminal β1,4-linked galactose, opposite to cell lines bearing multiple markers. These results suggest mechanisms whereby inflammation might influence tumor behavior in a cell-type specific manner through modulating the presentation of cancer-associated glycans.

Emerging potential of natural products for targeting mucins for therapy against inflammation and cancer

“…Resveratrol has been shown to sensitization of tumor cells to many chemotherapeutic drugs by modulating multiple cell-signaling molecules, including drug transporters and members of the NF –κB, SP1and STAT3 signaling pathways [140]. Our lab and others have conclusively established the involvement of NF-κB and STAT3 signaling pathways in regulating mucins expression particularly MUC1 and MUC4 (reviewed in[54, 55]. While these studies suggest that resveratrol mediated chemosensitization of cancer cells may be attributed to the modulation of mucin expression, a more direct association needs to be explored.…”

“…Previous studies have shown that a large array of pro-inflammatory cytokines and interleukins like IL-4, IL-9, IL-13 and tumor necrosis factor-α (TNF-α) secreted by lymphocytes during injury or infection results in aberrant mucin expression [54, 55]. Our studies and others have shown that MUC4 is transcriptionally regulated by inflammatory cytokines like interferon-γ (IFN-γ) [56] whereas MUC1/MUC5AC is regulated by neutrophil elastase respectively [57], a neutrophil secreted serine protease during inflammation [58].…”

“…In addition, TNF-α, IL-1β, IL-6 and IL-8 upregulate major gel-forming MUC19 transcript in the human middle ear [64]. Not only expression, mucin glycosylation patterns are also altered in response to pro-inflammatory conditions in cancer cells [55]. …”

“…MUC1 overexpression is considered to contribute to several epithelial malignancies and its transcriptional regulation has extensively been studied [54, 55]. The MUC1 promoter is GC-rich and contains numerous binding sites for specificity protein-1 (Sp1), activator protein-1 (AP-1), AP-2, AP-3, nuclear factor-1 (NF-1), estrogen receptor (ER) and signal transducers and activators of transcription (STAT) transcription factors [68].…”

The Detection and Discovery of Glycan Motifs in Biological Samples Using Lectins and Antibodies: New Methods and Opportunities

“…Li et al, 2011 ). The microarray strategy was useful for characterizing the variation in glycoforms on mucins in pancreatic cancer patients ( Yue, et al, 2009 ) and in stimulated cell lines ( Y. M. Wu, Nowack, Omenn, & Haab, 2009 ), and for probing the glycoforms of TIMP-1 ( D.…”