Targeting Aberrant Sialylation in Cancer Cells Using a Fluorinated Sialic Acid Analog Impairs Adhesion, Migration, and In Vivo Tumor Growth
Targeting Aberrant Sialylation in Cancer Cells Using a Fluorinated Sialic Acid Analog Impairs Adhesion, Migration, and In Vivo Tumor Growth
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DOI：
10.1158/1535-7163.mct-13-0279
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发表时间：
2013-10-01
影响因子：
5.7
通讯作者：
Adema, Gosse J.
中科院分区：
文献类型：
--
作者：
Bull, Christian;Boltje, Thomas J.;Adema, Gosse J.
癌细胞通过上调唾液酸转移酶和其他糖基因的表达，用唾液酸化聚糖的致密层装饰其表面。虽然唾液酸在许多生物过程中起着至关重要的作用，但特别是过度唾液酸化已被证明有助于癌细胞的进展和转移。因此，干扰唾液酸合成的选择性策略可能为癌症治疗提供强有力的方法。在本研究中，我们评估了最近开发的氟化唾液酸类似物（P-3F（ax）-Neu 5Ac）阻断小鼠黑色素瘤细胞中唾液酸聚糖合成的潜力，以及对细胞粘附、迁移和体内生长的影响。结果显示，P-3F（ax）-Neu 5Ac容易引起B16 F10细胞中α 2，3-/α 2，6-连接的唾液酸的消耗数天。长期抑制唾液酸化28天是可行的，而不影响细胞活力或增殖。此外，P-3F（ax）-Neu 5Ac被证明即使在高浓度的竞争性唾液酸转移酶底物下也是高度有效的唾液酸化抑制剂。P-3F（ax）-Neu 5Ac处理的癌细胞表现出与聚-L-赖氨酸、I型胶原和纤连蛋白的结合受损，迁移能力降低。最后，用这种新型唾液酸类似物阻断B16 F10肿瘤细胞的唾液酸化降低了它们在体内的生长。这些结果表明P-3F（ax）-Neu 5Ac是能够抑制异常唾液酸化的强大糖模拟物，其可潜在地用于抗癌疗法。(c)2013年AACR。
Cancer cells decorate their surface with a dense layer of sialylated glycans by upregulating the expression of sialyltransferases and other glycogenes. Although sialic acids play a vital role in many biologic processes, hypersialylation in particular has been shown to contribute to cancer cell progression and metastasis. Accordingly, selective strategies to interfere with sialic acid synthesis might offer a powerful approach in cancer therapy. In the present study, we assessed the potential of a recently developed fluorinated sialic acid analogue (P-3F(ax)-Neu5Ac) to block the synthesis of sialoglycans in murine melanoma cells and the consequences on cell adhesion, migration, and in vivo growth. The results showed that P-3F(ax)-Neu5Ac readily caused depletion of alpha 2,3-/alpha 2,6-linked sialic acids in B16F10 cells for several days. Long-term inhibition of sialylation for 28 days was feasible without affecting cell viability or proliferation. Moreover, P-3F(ax)-Neu5Ac proved to be a highly potent inhibitor of sialylation even at high concentrations of competing sialyltransferase substrates. P-3F(ax)-Neu5Ac-treated cancer cells exhibited impaired binding to poly-L-lysine, type I collagen, and fibronectin and diminished migratory capacity. Finally, blocking sialylation of B16F10 tumor cells with this novel sialic acid analogue reduced their growth in vivo. These results indicate that P-3F(ax)-Neu5Ac is a powerful glycomimetic capable of inhibiting aberrant sialylation that can potentially be used for anticancer therapy. (c) 2013 AACR.