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J. Biol. Chem. 286 (26): 22982-22990

© 2011 by The American Society for Biochemistry and Molecular Biology, Inc.

Sialylation of the Fas Death Receptor by ST6Gal-I Provides Protection against Fas-mediated Apoptosis in Colon Carcinoma Cells*

Amanda F. Swindall1, and Susan L. Bellis2

From the Department of Physiology and Biophysics, University of Alabama at Birmingham, Birmingham, Alabama 35294

ABSTRACT Back to Top

Abstract: The glycosyltransferase, ST6Gal-I, adds sialic acid in an α2–6 linkage to the N-glycans of membrane and secreted glycoproteins. Up-regulation of ST6Gal-I occurs in many cancers, including colon carcinoma, and correlates with metastasis and poor prognosis. However, mechanisms by which ST6Gal-I facilitates tumor progression remain poorly understood due to limited knowledge of enzyme substrates. Herein we identify the death receptor, Fas (CD95), as an ST6Gal-I substrate, and show that α2–6 sialylation of Fas confers protection against Fas-mediated apoptosis. Intriguingly, differences in ST6Gal-I activity do not affect the function of DR4 or DR5 death receptors upon treatment with TRAIL, implicating a selective effect of ST6Gal-I on the Fas receptor. Using ST6Gal-I knockdown and forced overexpression colon carcinoma cell models, we find that α2–6 sialylation of Fas prevents apoptosis stimulated by FasL as well as the Fas-activating antibody, CH11, as evidenced by decreased activation of caspases 8 and 3. We also show that α2–6 sialylation of Fas does not alter the binding of CH11, but rather inhibits the capacity of Fas to induce apoptosis by blocking the association of FADD with Fas cytoplasmic tails, an event that initiates death-inducing signaling complex formation. Furthermore, α2–6 sialylation of Fas inhibits Fas internalization, which is required for apoptotic signaling. Although dysregulated Fas activity is a well known mechanism through which tumors evade apoptosis, the current study is the first to link Fas insensitivity to the actions of a specific sialyltransferase. This finding establishes a new paradigm by which death receptor function is impaired for the self-protection of tumors against apoptosis.

Key Words: Apoptosis • Caspase • Cell Death • Colon Cancer • Glycoprotein • CD95 • Fas • ST6Gal-I • Death Receptor • Sialic Acid

Received for publication December 10, 2010. Revision received April 28, 2011.

FOOTNOTES Back to Top

1 Supported by the Howard Hughes Med-into-Grad Ph.D. program, as well as a pre-doctoral fellowship from the American Heart Association.

2 To whom correspondence should be addressed: 1918 University Blvd., 982A MCLM, Birmingham, AL 35294. Tel.: 205-934-3441; E-mail: bellis{at}uab.edu.

THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
ST6Gal-I Protein Expression Is Upregulated in Human Epithelial Tumors and Correlates with Stem Cell Markers in Normal Tissues and Colon Cancer Cell Lines.
A. F. Swindall, A. I. Londono-Joshi, M. J. Schultz, N. Fineberg, D. J. Buchsbaum, and S. L. Bellis (2013)
Cancer Res. 73, 2368-2378
   Abstract »    Full Text »    PDF »
ST6Gal-I Regulates Macrophage Apoptosis via {alpha}2-6 Sialylation of the TNFR1 Death Receptor.
Z. Liu, A. F. Swindall, R. A. Kesterson, T. R. Schoeb, D. C. Bullard, and S. L. Bellis (2011)
J. Biol. Chem. 286, 39654-39662
   Abstract »    Full Text »    PDF »

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