Research Papers:
SMAD4-independent activation of TGF-β signaling by MUC1 in a human pancreatic cancer cell line
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Abstract
Priyanka Grover1,*, Sritama Nath1,*, Monica D. Nye1, Ru Zhou1, Mohammad Ahmad1 and Pinku Mukherjee1
1Department of Biological Sciences, University of North Carolina at Charlotte, Charlotte, North Carolina 28223-0001, USA
*These authors have contributed equally to this work
Correspondence to:
Pinku Mukherjee, email: [email protected]
Keywords: apoptosis; epithelial-mesenchymal transition (EMT); transforming growth factor beta (TGF-β); pancreatic cancer; mucin 1 (MUC1)
Received: January 20, 2017 Accepted: December 18, 2017 Published: January 05, 2018
ABSTRACT
Pancreatic Ductal Adenocarcinoma (PDA) has a mortality rate that nearly matches its incidence rate. Transforming Growth Factor Beta (TGF-β) is a cytokine with a dual role in tumor development switching from a tumor suppressor to a tumor promoter. There is limited knowledge of how TGF-β function switches during tumorigenesis. Mucin 1 (MUC1) is an aberrantly glycosylated, membrane-bound, glycoprotein that is overexpressed in >80% of PDA cases and is associated with poor prognosis. In PDA, MUC1 promotes tumor progression and metastasis via signaling through its cytoplasmic tail (MUC1-CT) and interacting with other oncogenic signaling molecules. We hypothesize that high levels of MUC1 in PDA may be partly responsible for the TGF-β functional switch during oncogenesis. We report that overexpression of MUC1 in BxPC3 human PDA cells (BxPC3.MUC1) enhances the induction of epithelial to mesenchymal transition leading to increased invasiveness in response to exogenous TGF-β1. Simultaneously, these cells resist TGF-β induced apoptosis by downregulating levels of cleaved caspases. We show that mutating the tyrosines in MUC1-CT to phenylalanine reverses the TGF-β induced invasiveness. This suggests that the tyrosine residues in MUC1-CT are required for TGF-β induced invasion. Some of these tyrosines are phosphorylated by the tyrosine kinase c-Src. Thus, treatment of BxPC3.MUC1 cells with a c-Src inhibitor (PP2) significantly reduces TGF-β induced invasiveness. Similar observations were confirmed in the Chinese hamster ovarian (CHO) cell line. Data strongly suggests that MUC1 may regulate TGF-β function in PDA cells and thus have potential clinical relevance in the use of TGF-β inhibitors in clinical trials.
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