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.