The Glycosyltransferase ST6Gal-I Protects Tumor Cells against Serum Growth Factor Withdrawal by Enhancing Survival Signaling and Proliferative Potential

• Published in: The Journal of biological chemistry Vol. 292; no. 11; pp. 4663 - 4673
• Main Authors: Britain, Colleen M., Dorsett, Kaitlyn A., Bellis, Susan L.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 17-03-2017; American Society for Biochemistry and Molecular Biology
• Subjects: Antigens, CD - genetics; Antigens, CD - metabolism; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Cell Survival; Cyclin D2 - genetics; Gene Expression Regulation, Neoplastic; Glycobiology and Extracellular Matrices; glycosylation; growth factor; Humans; Intercellular Signaling Peptides and Proteins - blood; Intercellular Signaling Peptides and Proteins - metabolism; Neoplasms - blood; Neoplasms - genetics; Neoplasms - metabolism; NF-kappa B - metabolism; Serum - metabolism; sialyltransferase; Sialyltransferases - genetics; Sialyltransferases - metabolism; Signal Transduction; Up-Regulation; β-galactoside α-2,6-sialyltransferase 1 (ST6Gal-I); growth factor; glycosylation; cell cycle; β-galactoside α-2,6-sialyltransferase 1 (ST6Gal-I); sialyltransferase
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M116.763862

A hallmark of cancer cells is the ability to survive and proliferate when challenged with stressors such as growth factor insufficiency. In this study, we report a novel glycosylation-dependent mechanism that protects tumor cells from serum growth factor withdrawal. Our results suggest that the β-galactoside α-2,6-sialyltransferase 1 (ST6Gal-I) sialyltransferase, which is up-regulated in numerous cancers, promotes the survival of serum-starved cells. Using ovarian and pancreatic cancer cell models with ST6Gal-I overexpression or knockdown, we find that serum-starved cells with high ST6Gal-I levels exhibit increased activation of prosurvival signaling molecules, including pAkt, p-p70S6K, and pNFκB. Correspondingly, ST6Gal-I activity augments the expression of tumor-promoting pNFκB transcriptional targets such as IL-6, IL-8, and the apoptosis inhibitor cIAP2. ST6Gal-I also potentiates expression of the cell cycle regulator cyclin D2, leading to increased phosphorylation and inactivation of the cell cycle inhibitor pRb. Consistent with these results, serum-starved cells with high ST6Gal-I expression maintain a greater number of S phase cells compared with low ST6Gal-I expressors, reflecting enhanced proliferation. Finally, selective enrichment in clonal variants with high ST6Gal-I expression is observed upon prolonged serum deprivation, supporting the concept that ST6Gal-I confers a survival advantage. Collectively, these results implicate a functional role for ST6Gal-I in fostering tumor cell survival within the serum-depleted tumor microenvironment.