Hypothesis: Hypoxia inducesde novosynthesis of NeuGc gangliosides in humans through CMAH domain substitute

Abstract

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.

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“…Consequently, humans are only able to produce Neu5Ac de novo, although several studies have demonstrated that trace levels of Neu5Gc is present in human tissues [7][8][9][10]. It is thought that the Neu5Gc present in normal human tissue may come from dietary sources such as red meat and dairy products [10,11], although novel pathways have been proposed that may reactivate the defective CMAH protein under certain conditions [12]. Neu5Ac is present in every human cell type, and it is involved in cell-cell adhesion, signalling and immunity, discriminating 'self from 'non-self ' [13].…”