Inhibition of hepatocellular carcinoma growth by blockade of glycosphingolipid synthesis

Abstract

Hepatocellular carcinoma (HCC) is one of the most frequent cancers. <i>In vitro</i> studies suggest that growth and response to therapy of human carcinomas may depend on glycosphingolipid (GSL) expression. Glucosylceramide synthase (GCS), encoded by the gene <i>Ugcg</i>, is the basic enzyme required for the synthesis of GSLs. Gene array analysis implied that <i>Ugcg</i> is significantly overexpressed in human HCC as compared to non-tumorous liver tissue. Therefore we have investigated whether tumor - genesis and - growth is altered in the absence of GSLs. An endogenous liver cancer model has been initiated by application of diethylnitrosamine in mice lacking <i>Ugcg</i> specifically in hepatocytes. We have now shown that hepatocellular tumor initiation and growth in mice is significantly inhibited by hepatic GSL deficiency <i>in vivo</i>. Neither the expression of cell cycle proteins, such as cyclins and pathways such as the MAP-kinase/Erk pathway nor the mTOR/Akt pathway as well as the number of liver infiltrating macrophages and T cells were essentially changed in tumors lacking GSLs. Significantly elevated bi-nucleation of atypical hepatocytes, a feature for impaired cytokinesis, was detected in tumors of mice lacking liver-specific GSLs. A reduction of proliferation and restricted growth of tumor microspheres due to delayed, GSL-dependent cytokinesis, analogous to the histopathologic phenotype <i>in vivo</i> could be demonstrated <i>in vitro</i>. GSL synthesis inhibition may thus constitute a potential therapeutic target for hepatocellular carcinoma.