g(m2)-ganglioside and Brain-Neoplasms

GRP94 is an ATP-dependent chaperone able to regulate pro-oncogenic signaling pathways. Previous studies have shown a critical role of GRP94 in brain metastasis (BrM) pathogenesis and progression. In this work, an untargeted lipidomic analysis revealed that some lipid species were altered in GRP94-deficient cells, specially GM2 and GM3 gangliosides. The catalytic pathway of GM2 is affected by the low enzymatic activity of β-Hexosaminidase (HexA), responsible for the hydrolysis of GM2 to GM3. Moreover, a deficiency of the GM2-activator protein (GM2-AP), the cofactor of HexA, is observed without alteration of gene expression, indicating a post-transcriptional alteration of GM2-AP in the GRP94-ablated cells. One plausible explanation of these observations is that GM2-AP is a client of GRP94, resulting in defective GM2 catabolic processing and lysosomal accumulation of GM2 in GRP94-ablated cells. Overall, given the role of gangliosides in cell surface dynamics and signaling, their imbalance might be linked to modifications of cell behaviour acquired in BrM progression. This work indicates that GM2-AP could be an important factor in ganglioside balance maintenance. These findings highlight the relevance of GM3 and GM2 gangliosides in BrM and reveal GM2-AP as a promising diagnosis and therapeutic target in BrM research.

Topics: Animals; beta-Hexosaminidase alpha Chain; Brain Neoplasms; Carcinoma; Cell Line, Tumor; Culture Media, Conditioned; Down-Regulation; Female; G(M2) Activator Protein; G(M2) Ganglioside; G(M3) Ganglioside; Gene Expression Regulation, Neoplastic; Genes, Reporter; Humans; Lipidomics; Lysosomes; Membrane Glycoproteins; Mice; Neoplasm Proteins; RNA Interference; RNA, Small Interfering; Triple Negative Breast Neoplasms

The content of serum gangliosides was examined in VM and C57BL/6J (B6) mice that contained subcutaneous metastatic (VM) and non-metastatic (CT-2A) brain tumors, respectively. Gas-liquid chromatography (GLC) and high performance thin-layer chromatography (HPTLC) were used to analyze the serum gangliosides. N-glycolylneuraminic acid (NeuGc) accounted for greater than 90% of the total serum sialic acid content in each mouse strain (5.53 nmol and 2.05 nmol per ml serum, respectively). GM2-NeuGc was the major serum ganglioside detectable in both the normal and tumor-bearing mice of each strain. Shedding of tumor gangliosides into the serum occurs in various murine non-neural tumors and in human gliomas and neuroblastomas, but has not been previously studied in murine brain tumors. Our results show that serum ganglioside concentration was reduced in VM mice bearing the metastatic VM tumor, but was increased in B6 mice bearing the non-metastatic CT-2A tumor. These changes in concentration, however, were not associated with marked changes in serum ganglioside distribution. As serum gangliosides are synthesized in the liver, the differences in serum ganglioside concentration in the tumor-bearing mice may arise more from changes in liver function than from differences in tumor shedding.

Topics: Animals; Brain Neoplasms; Female; G(M2) Ganglioside; Gangliosides; Male; Mice; Mice, Inbred C57BL; Neoplasm Transplantation