Gangliosides of liver tumors induced by N-2-fluorenylacetamide. II. Alterations in biosynthetic enzymes.
Gangliosides of liver tumors induced by N-2-fluorenylacetamide. II. Alterations in biosynthetic enzymes.
复制标题
N-2-芴基乙酰胺诱导的肝肿瘤神经节苷脂。
DOI：
10.1093/jnci/60.6.1329
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发表时间：
1978
期刊：
影响因子：
--
通讯作者：
T. W. Keenan
中科院分区：
文献类型：
--
作者：
W. Merritt;D. Morré;T. W. Keenan
在N-2-芴乙酰胺诱导的肿瘤发生过程中，单唾液酸神经节苷脂途径的酶活性[乳糖神经酰胺→N-乙酰神经氨酸（唾液酸）（NAN）-半乳糖（Gal）-N-乙酰半乳糖胺（GalNAc）-（NAN）-Gal-葡萄糖（Glc）-神经酰胺（Cer）（GD1a）]逐渐升高至高于对照肝脏的酶活性癌前组织和分化良好的肝癌。 UDP-Gal:GalNAc-(NAN)-Gal-Glc-Cer (GM2) 半乳糖基转移酶和 CMP-NAN:Gal-GalNAc-(NAN)-Gal-Glc-Cer (GM1) 唾液酸转移酶的活性与早期肿瘤生长直接相关。生物合成序列中第一个酶 CMP-NAN：乳糖神经酰胺唾液酸转移酶的活性在癌前肝组织和增生结节中升高 2.5 倍，并且在高分化和低分化肝癌中保持接近该水平。 UDP-GalNAc:NAN-Gal-Glc-Cer (GM3)N-乙酰半乳糖氨基转移酶在结节和肝癌周围组织以及边界清楚、分化差的肝癌中升高，但在结节中降低。 CMP-NAN 未并入任何组织中的 GD1a。在各种类型的肿瘤中，单唾液酸神经节苷脂途径的合成酶活性的相对水平与该途径分支中的糖脂水平相关。正常大鼠肝脏含有高水平的二唾液酸神经节苷脂途径的酶，其中四唾液酸神经节苷脂是由苏木苷通过二唾液酸神经节苷脂中间体合成的。在所有肝癌类型中，分支点酶 CMPNAN：GM3 唾液酸转移酶的比活性通常显着低于对照肝脏，并且在三个边界清楚、分化差的肝癌中的两个中观察到 CMP-NAN：Gal-GalNAc-(NAN)2-Gal-Glc-Cer (GD1b) 唾液酸转移酶的丢失。双唾液酸神经节苷脂途径的其他生物合成酶，UDP-GalNAc:(NAN)2-Gal-Glc-CerN-乙酰半乳糖氨基转移酶和UDP-Gal:GalNAc(NAN)2-Gal-Glc-Cer半乳糖基转移酶的比活性在这些相同肿瘤中接近或高于对照活性。分支点酶的缺乏可能是肝癌特征性 GM1+ GD1ato GD1b+ GT[NAN-Gal-GalNAc-(NAN)2-Gal-Glc-Cer 或 (NAN)3-Gal-Glc-Cer] 比例逐渐升高的潜在重要因素。这些发现表明，肿瘤发生过程中糖脂的变化是其各自生物合成酶活性变化的直接反映。
Activities of the enzymes of the monosialoganglioside pathway [lactosylceramide →N-acetylneuraminic acid (sialic acid) (NAN)-galactose (Gal)-N-acetylgalactosamlne (GalNAc)-(NAN)-Gal-glucose (Glc)-ceramide (Cer) (GD1a)] were elevated progressively above those of control liver during tumorigenesis induced byN-2-fluorenylacetamide in precancerous tissues and well-differentiated hepatomas. The activities of UDP-Gal:GalNAc-(NAN)-Gal-Glc-Cer (GM2) galactosyltransferase and, to a lesser extent, CMP-NAN:Gal-GalNAc-(NAN)-Gal-Glc-Cer (GM1) sialyltransferase were correlated directly with early tumor growth. Activities of the first enzyme in the biosynthetic sequence, the CMP-NAN:lactosylceramide sialyltransferase, were elevated 2.5-fold in precancerous liver tissues and hyperplastic nodules and remained near that level in well-differentiated and poorly differentiated hepatomas. The UDP-GalNAc:NAN-Gal-Glc-Cer (GM3)N-acetylgalactosaminyltransferase was elevated in tissues surrounding nodules and hepatomas as well as in well-circumscribed, poorly differentiated hepatomas, but it was depressed in nodules. CMP-NAN was not incorporated into GD1ain any tissue. In the various types of tumors, the relative levels of activities of blosynthetic enzymes of the monosialoganglioside pathway correlated with the glycolipid levels in this branch of the pathway. Normal rat liver contained high levels of the enzymes of the disialoganglioside pathway in which tetrasialoganglioside is synthesized from hematoside via disialoganglioside intermediates. Specific activities of the branch-point enzyme CMPNAN: GM3 sialyltransferase were generally significantly lower than those of control livers in all hepatoma types, and a loss of CMP-NAN: Gal-GalNAc-(NAN)2-Gal-Glc-Cer (GD1b) sialyltransferase was observed in two of three well-circumscribed, poorly differentiated hepatomas. The specific activities of other biosynthetic enzymes of the disialoganglioside pathway, UDP-GalNAc:(NAN)2-Gal-Glc-CerN-acetylgalactosaminyltransferase and UDP-Gal:GalNAc(NAN)2-Gal-Glc-Cer galactosyltransferase, were either near or above control activities in these same tumors. Deficiency of the branch-point enzyme may be a potentially important contributor to the progressive rise in the ratio of GM1+ GD1ato GD1b+ GT[NAN-Gal-GalNAc-(NAN)2-Gal-Glc-Cer or (NAN)3-Gal-Glc-Cer] characteristic of hepatomas. These findings suggested that glycolipid alterations during tumorigenesis are a direct reflection of alterations in the activities of their respective biosynthetic enzymes.