The Glycosyltransferase ST6Gal-I Protects Tumor Cells against Serum Growth Factor Withdrawal by Enhancing Survival Signaling and Proliferative Potential.
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.
From the Department of Cell, Developmental, and Integrative Biology, University of Alabama at Birmingham, Birmingham, Alabama 35294.
Colleen M
CM
Britain
From the Department of Cell, Developmental, and Integrative Biology, University of Alabama at Birmingham, Birmingham, Alabama 35294.
Kaitlyn A
KA
Dorsett
From the Department of Cell, Developmental, and Integrative Biology, University of Alabama at Birmingham, Birmingham, Alabama 35294 bellis@uab.edu.
Susan L
SL
Bellis
D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism*; D002453:Cell Cycle; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival; D056742:Cyclin D2 / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000097:blood / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D009369:Neoplasms / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D044967:Serum / Q000378:metabolism; D012799:Sialyltransferases / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D015854:Up-Regulation; D000094802:beta-D-Galactoside alpha 2-6-Sialyltransferase
D015703:Antigens, CD; D056742:Cyclin D2; D036341:Intercellular Signaling Peptides and Proteins; D016328:NF-kappa B; D012799:Sialyltransferases; C093493:ST6GAL1 protein, human; D000094802:beta-D-Galactoside alpha 2-6-Sialyltransferase
cell cycle; glycosylation; growth factor; sialyltransferase; β-galactoside α-2,6-sialyltransferase 1 (ST6Gal-I)