Abstract 2334: Sialylation of the TNFR1 death receptor promotes cancer cell survival
| Autor: | Zhongyu Liu, Susan L. Bellis, Matthew J. Schultz, Andrew T. Holdbrooks, Daniel C. Bullard |
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| Rok vydání: | 2018 |
| Předmět: | |
| Zdroj: | Cancer Research. 78:2334-2334 |
| ISSN: | 1538-7445 0008-5472 |
| Popis: | Studies have well-established that activation of TNFR1, a ubiquitously expressed cell surface receptor, by TNF can induce either cell survival or cell death signaling cascades, however, the mechanisms regulating TNFR1 to initiate these disparate outcomes are poorly understood. TNF-induced apoptosis is initiated by clustering of activated TNFR1 at the cell surface, followed by internalization of the receptor complexes and subsequent caspase activation. Conversely, surface retention of activated TNFR1 promotes cell survival signaling mediated by NFκB and MAPKs pathways. Our group has identified a glycosylation-dependent mechanism that controls this TNFR1 signaling switch (i.e. apoptosis vs. survival). Specifically, we have found that TNFR1 activity is modified by the addition of a distinct sugar, an α2-6 linked sialic acid, by the Golgi sialyltransferase, ST6Gal-I. Importantly, ST6Gal-I is highly upregulated in numerous cancer types, and through its sialylation of a select cohort of cell surface receptors, various studies have indicated ST6Gal-I as a potent tumor cell survival factor. The effect of sialylation on TNFR1 was examined in multiple cancer cell models, including leukemia and epithelial cancer cell lines with forced overexpression or knockdown of ST6Gal-I. These models show that TNFR1 sialylation blocks TNF-induced apoptosis (indicated by the inhibition of caspase activation), and data from our group suggests that the underlying mechanism of this inhibition of apoptosis involves the sialylation-driven interference of TNFR1 oligomerization and internalization. Considering sialylated TNFR1 is retained on the cell surface following activation, we hypothesize that cells with abundant ST6Gal-I not only block TNFR1-mediated apoptosis but also divert signaling towards survival, indicated by increased activity and expression of many pro-survival factors (NFkB, AKT, etc.). Based on these collective findings, we conclude that the ST6Gal-I-mediated sialylation of TNFR1 controls the cellular response to TNF by blocking TNFR1 internalization, resulting in apoptosis inhibition and the promotion of survival signaling. Considering the tumor microenvironment is rich in immune cell-derived TNF, we posit that ST6Gal-I protects tumor cells within this inflammatory milieu by providing a mechanism by which tumor cells can evade immune cell killing. Citation Format: Andrew T. Holdbrooks, Matthew J. Schultz, Zhongyu Liu, Daniel C. Bullard, Susan L. Bellis. Sialylation of the TNFR1 death receptor promotes cancer cell survival [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2334. |
| Databáze: | OpenAIRE |
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