Hypothesis: Hypoxia induces de novo synthesis of NeuGc gangliosides in humans through CMAH domain substitute
Hypothesis: Hypoxia induces de novo synthesis of NeuGc gangliosides in humans through CMAH domain substitute
复制标题
DOI：
10.1016/j.bbrc.2017.11.183
复制
发表时间：
2018-01-01
影响因子：
3.1
通讯作者：
Krengel, Ute
中科院分区：
文献类型：
--
作者：
Bousquet, Paula A.;Sandvik, Joe Alexander;Krengel, Ute
免疫治疗是癌症研究中一个不断发展的领域。一种备受关注的特权肿瘤相关抗原是N-乙醇基(NeuGc)GM3。这种神经节苷脂存在于几种类型的癌症中，但在人类健康组织中几乎检测不到。然而，它的非羟化变异体NeuAc GM3在所有哺乳动物中都有丰富的存在。由于人类编码合成NeuGc的关键酶的基因缺失，与其他哺乳动物相比，人类不能合成NeuGc GM3。因此，这种神经节苷脂在人类癌细胞中的存在是一个谜。已有研究表明，在低氧条件下，NeuGc神经节苷脂表达增强，不仅可作为肿瘤治疗的靶点，而且可作为肿瘤诊断和预后的标记物。在这里，我们证实了低氧诱导的NeuGc GM3神经节苷脂在HeLa细胞中的表达，并揭示了几个候选蛋白质，特别是GM3合成酶和呼吸复合体II(SDHB)的B亚基，通过基于SILAC的蛋白质组分析，它们可能参与了NeuGc GM3的产生。这些发现有可能显著提高我们对这种神秘的肿瘤相关抗原在人类中是如何产生的理解，并提示识别缺氧标志物的抗肿瘤抗体的可能作用机制，如14F7。(C)2017 Elsevier Inc.保留所有权利。
Immunotherapy is a growing field in cancer research. A privileged tumor-associated antigen that has received much attention is N-glycolyl (NeuGc) GM3. This ganglioside is present in several types of cancer, but is almost undetectable in human healthy tissues. However, its non-hydroxylated variant, NeuAc GM3, is abundant in all mammals. Due to a deletion in the human gene encoding the key enzyme for synthesis of NeuGc, humans, in contrast to other mammals, cannot synthesize NeuGc GM3. Therefore the presence of this ganglioside in human cancer cells represents an enigma. It has been shown that hypoxic conditions trigger the expression of NeuGc gangliosides, which not only serve as attractive targets for cancer therapy, but also as diagnostic and prognostic tumor marker. Here, we confirm hypoxia-induced expression of the NeuGc GM3 ganglioside also in HeLa cells and reveal several candidate proteins, in particular GM3 synthase and subunit B of respiratory complex II (SDHB), that may be involved in the generation of NeuGc GM3 by SILAC-based proteome analysis. These findings have the potential to significantly advance our understanding of how this enigmatic tumor-associated antigen is produced in humans, and also suggest a possible mechanism of action of anti-tumor antibodies that recognize hypoxia markers, such as 14F7. (C) 2017 Elsevier Inc. All rights reserved.