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

Abstract

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.

• Authors: Colleen M Britain, Kaitlyn A Dorsett, Susan L Bellis
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 292 Issue 11 Pg. 4663-4673 (03 17 2017) ISSN: 1083-351X [Electronic] United States
• PMID: 28154177 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

Chemical References

• Antigens, CD
• Cyclin D2
• Intercellular Signaling Peptides and Proteins
• NF-kappa B
• Sialyltransferases
• ST6GAL1 protein, human

Topics

• Antigens, CD (genetics, metabolism)
• Cell Cycle
• Cell Line, Tumor
• Cell Proliferation
• Cell Survival
• Cyclin D2 (genetics)
• Gene Expression Regulation, Neoplastic
• Humans
• Intercellular Signaling Peptides and Proteins (blood, metabolism)
• NF-kappa B (metabolism)
• Neoplasms (blood, genetics, metabolism)
• Serum (metabolism)
• Sialyltransferases (genetics, metabolism)
• Signal Transduction
• Up-Regulation