Inhibition of Ganglioside Synthesis Suppressed Liver Cancer Cell Proliferation through Targeting Kinetochore Metaphase Signaling

Abstract

The incidence and mortality of liver cancer, mostly hepatocellular carcinoma (HCC), have increased during the last two decades, partly due to persistent inflammation in the lipid-rich microenvironment associated with lifestyle diseases, such as obesity. Gangliosides are sialic acid-containing glycosphingolipids known to be important in the organization of the membrane and membrane protein-mediated signal transduction. Ganglioside synthesis is increased in several types of cancers and has been proposed as a promising target for cancer therapy. Here, we provide evidence that ganglioside synthesis was increased in the livers of an animal model recapitulating the features of activation and expansion of liver progenitor-like cells and liver cancer (stem) cells. Chemical inhibition of ganglioside synthesis functionally suppressed proliferation and sphere growth of liver cancer cells, but had no impact on apoptotic and necrotic cell death. Proteome-based mechanistic analysis revealed that inhibition of ganglioside synthesis downregulated the expression of AURKA, AURKB, TTK, and NDC80 involved in the regulation of kinetochore metaphase signaling, which is essential for chromosome segregation and mitotic progression and probably under the control of activation of TP53-dependent cell cycle arrest. These data suggest that targeting ganglioside synthesis holds promise for the development of novel preventive/therapeutic strategies for HCC treatment.