ST6Gal-I sialyltransferase promotes tumor necrosis factor (TNF)-mediated cancer cell survival via sialylation of the TNF receptor 1 (TNFR1) death receptor
ST6Gal-I sialyltransferase promotes tumor necrosis factor (TNF)-mediated cancer cell survival via sialylation of the TNF receptor 1 (TNFR1) death receptor
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DOI：
10.1074/jbc.m117.801480
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发表时间：
2018-02-02
影响因子：
4.8
通讯作者：
Bellis, Susan L.
中科院分区：
文献类型：
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作者：
Holdbrooks, Andrew T.;Britain, Colleen M.;Bellis, Susan L.
TNF激活肿瘤坏死因子受体1 （TNFR1）死亡受体可诱导细胞存活或死亡。然而，介导这些不同结果的机制仍然知之甚少。在这项研究中，我们报道了ST6Gal-I唾液转移酶，一种在许多癌症中上调的酶，唾液化TNFR1，从而保护肿瘤细胞免受tnf诱导的凋亡。使用ST6Gal-I敲低或过表达的胰腺癌和卵巢癌细胞，我们确定TNFR1的2-6唾液化对tnf诱导的早期信号事件没有影响，包括NF-B、c-Jun n末端激酶（JNK）、细胞外信号调节激酶（ERK）和Akt的快速激活（发生在15分钟内）。然而，在延长TNF处理时间（6-24小时）后，高ST6Gal-I水平的细胞表现出对TNF诱导的凋亡的抗性，形态学证据表明细胞死亡和caspases 8和3的激活降低。相应地，在这些较晚的时间点，ST6Gal-I高表达者表现出存活分子Akt和NF-B的持续激活。此外，延长TNF治疗导致ST6Gal-I高表达的克隆变异选择性富集，进一步证实了ST6Gal-I在细胞存活中的作用。考虑到TNFR1内化对于诱导细胞凋亡至关重要，而生存信号是由质膜上的TNFR1启动的，我们研究了TNFR1的定位。研究发现，TNFR1的2-6唾液化可抑制tnf诱导的TNFR1内化。因此，通过唾液化抑制细胞表面的TNFR1， ST6Gal-I作为一个功能开关，将信号转向生存。这些共同的发现指出了一种新的糖基化依赖机制，该机制调节细胞对TNF的反应，并可能促进癌细胞在富含TNF的肿瘤微环境中存活。
Activation of the tumor necrosis factor receptor 1 (TNFR1) death receptor by TNF induces either cell survival or cell death. However, the mechanisms mediating these distinct outcomes remain poorly understood. In this study, we report that the ST6Gal-I sialyltransferase, an enzyme up-regulated in numerous cancers, sialylates TNFR1 and thereby protects tumor cells from TNF-induced apoptosis. Using pancreatic and ovarian cancer cells with ST6Gal-I knockdown or overexpression, we determined that 2-6 sialylation of TNFR1 had no effect on early TNF-induced signaling events, including the rapid activation of NF-B, c-Jun N-terminal kinase (JNK), extracellular signal-regulated kinase (ERK), and Akt (occurring within 15 min). However, upon extended TNF treatment (6-24 h), cells with high ST6Gal-I levels exhibited resistance to TNF-induced apoptosis, as indicated by morphological evidence of cell death and decreased activation of caspases 8 and 3. Correspondingly, at these later time points, high ST6Gal-I expressers displayed sustained activation of the survival molecules Akt and NF-B. Additionally, extended TNF treatment resulted in the selective enrichment of clonal variants with high ST6Gal-I expression, further substantiating a role for ST6Gal-I in cell survival. Given that TNFR1 internalization is known to be essential for apoptosis induction, whereas survival signaling is initiated by TNFR1 at the plasma membrane, we examined TNFR1 localization. The 2-6 sialylation of TNFR1 was found to inhibit TNF-induced TNFR1 internalization. Thus, by restraining TNFR1 at the cell surface via sialylation, ST6Gal-I acts as a functional switch to divert signaling toward survival. These collective findings point to a novel glycosylation-dependent mechanism that regulates the cellular response to TNF and may promote cancer cell survival within TNF-rich tumor microenvironments.