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

Ting Su,Yutaka Furutani,Wenkui Yu,Soichi Kojima,Feifei Wei,Xian-Yang Qin,Naoshi Dohmae

doi:10.3390/metabo11030167

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.

Highlights

To further explore the changes of ganglioside synthesis in the liver of DDC-fed mice, the levers of GM1 ganglioside in murine livers were measured by immunofluorescence staining with cholera toxin subunit B (CTB), which is a heat-labile enterotoxin and has been widely used as a molecular probe to detect binding to ganglioside GM1 due to its high binding affinity [26]
As a proof of concept, direct profiling of tissue lipids using matrix-assisted laser desorption and ionization time-of-flight mass spectrometry (MALDI-TOFMS) demonstrated that the contents of ceramide (d18:0/16:0, 504.513 m/z), GM1 ganglioside (18:1/18:0, 797.746 m/z), and glucosylceramides (d18:1/25:0, 848.765 m/z; d18:1/26:1, 870.741 m/z) were increased in the livers of DDC-fed mice than those in chow-fed mice (Figure S2). These data suggested that the increased ganglioside synthesis in DDC-induced liver injury was related to the progenitor response, which is critical for liver tumorigenesis [28]
Our study showed that inhibition of ganglioside synthesis suppressed cell proliferation and sphere growth of hepatocellular carcinoma (HCC) cells, partly by targeting key regulators of mitosis, such as AURKB, TTK, and NDC80, which are involved in kinetochore metaphase signaling

Summary

Introduction

The global cancer mortality has decreased during the last two decades, both the incidence and disease-specific mortality of liver cancer in both sexes have increased, constituting an urgent need to develop efficient and safe preventive and therapeutic treatments [2,3]. Mature hepatocytes exhibit remarkable plasticity by direct dedifferentiation into an undifferentiated state in the chronic liver injury microenvironment, which are believed to represent the cells of origin, namely cancer stem cells (CSC), for liver cancer and are related to lipid metabolism reprogramming [9,10]. Understanding the changes and functions of lipid metabolism reprogramming during liver tumorigenesis will shed light on the development of novel therapeutic strategies for HCC treatment

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