Glycosyltransferase ST6Gal-I protects tumor cells against serum growth factor withdrawal by enhancing survival signaling and proliferative potential [Signal Transduction]

A hallmark of cancer cells is the ability to survive and proliferate when challenged with stressors such as growth factor insufficiency. In the current study we report a novel glycosylation-dependent mechanism that protects tumor cells from serum growth factor withdrawal. Results herein suggest that the ST6Gal-I sialyltransferase, which is upregulated 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 pro-survival signaling molecules including pAkt, p-p70S6K and pNFkB. Correspondingly, ST6Gal-I activity augments expression of tumor-promoting NFkB 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.

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