Molecular mechanism for cancer-associated induction of sialyl Lewis X and sialyl Lewis A expression - The Warburg effect revisited
Molecular mechanism for cancer-associated induction of sialyl Lewis X and sialyl Lewis A expression - The Warburg effect revisited
复制标题
DOI：
10.1023/b:glyc.0000033631.35357.41
复制
发表时间：
2003-01-01
影响因子：
3
通讯作者：
Kannagi, R
中科院分区：
文献类型：
--
作者：
Kannagi, R
由选择素及其碳水化合物配体sialyl刘易斯X和sialyl刘易斯A介导的细胞粘附在癌症转移中起重要作用。这些碳水化合物决定簇的表达在癌细胞中显著增强，但导致唾液酸刘易斯X/A的癌症相关表达的分子机制尚未得到很好的理解。最近的研究结果表明，在癌症中唾液酸刘易斯X/A的加速表达中涉及两种主要机制：“不完全合成”和“新合成”。至于“不完全合成”，我们最近在非恶性结肠上皮中发现了唾液酸刘易斯X和唾液酸刘易斯A的进一步修饰形式，它们具有额外的6-硫酸化或2 -> 6唾液酸化。恶性转化时GlcNAc 6-硫酸化和2 -> 6唾液酸化的损伤导致唾液酸刘易斯X/A在结肠癌细胞中的积累。表观遗传变化，如DNA甲基化和/或组蛋白脱乙酰化被认为是这种不完全合成的原因。至于称为“新合成”的机制，最近的研究表明，与癌症相关的糖转运和中间碳水化合物代谢的改变起着重要作用。已知癌细胞表现出从氧化糖酵解到升高的无氧糖酵解的代谢转变（瓦尔堡效应），这与由常见癌症特异性遗传改变诱导的糖转运蛋白和糖酵解酶的基因表达增加相关。癌症中唾液酸化刘易斯X/A表达的增加是这些事件链中的一个环节，因为我们最近的研究结果表明，这些事件伴随着一组与其表达密切相关的基因的转录诱导。
Cell adhesion mediated by selectins and their carbohydrate ligands, sialyl Lewis X and sialyl Lewis A, figures heavily in cancer metastasis. Expression of these carbohydrate determinants is markedly enhanced in cancer cells, but the molecular mechanism that leads to cancer-associated expression of sialyl Lewis X/A has not been well understood. Results of recent studies indicated involvement of two principal mechanisms in the accelerated expression of sialyl Lewis X/A in cancers; 'incomplete synthesis' and 'neosynthesis.' As to 'incomplete synthesis,' we have recently found further modified forms of sialyl Lewis X and sialyl Lewis A in non-malignant colonic epithelium, which have additional 6-sulfation or 2 --> 6 sialylation. The impairment of GlcNAc 6-sulfation and 2 --> 6 sialylation upon malignant transformation leads to accumulation of sialyl Lewis X/A in colon cancer cells. Epigenetic changes such as DNA methylation and/or histone deacetylation are suggested to lie behind such incomplete synthesis. As to the mechanism called 'neosynthesis,' recent studies have indicated that cancer-associated alterations in the sugar transportation and intermediate carbohydrate metabolism play important roles. Cancer cells are known to exhibit a metabolic shift from oxidative to elevated anaerobic glycolysis (Warburg effect), which is correlated with the increased gene expression of sugar transporters and glycolytic enzymes induced by common cancer-specific genetic alterations. The increased sialyl Lewis X/A expression in cancer is a link in the chains of these events because our recent results indicated that these events accompany transcriptional induction of a set of genes closely related to its expression.