ROLE OF GANGLIOSIDES IN MODULATING THE MOTILITY OF HUMAN CANCER CELLS

Abstract

Glycosphingolipids, due to their tendency to form laterally separated liquid-ordered phases, possess a high potential for the creation of order in biological membranes. The formation of glycosphingolipid-rich membrane domains within the membrane has profound consequences on the membrane organization at different levels, and on the conformational and biological properties of membrane-associated proteins and multimolecular protein complexes. Alterations in the structures of carbohydrate epitopes associated with glycosphingolipids are a common feature of tumors and tumor cells (“aberrant glycosylation”). In particular, tumors are characterized by the peculiar ability to manipulate sialylation processes (1). This abnormal sialylation process generates peculiar antigenic determinants, which are normally absent in healthy cells, and affects cell homeostasis, altering the normal signaling pathways. Indeed, glycosphingolipids in tumor cells have been implicated in the regulation of cell adhesion, motility, recognition, survival and proliferation (2). Thus, an ever-increasing interest to this regard is being devoted to gangliosides, sialic acid-containing glycolipids, and to the enzymes affecting sialylation. Both sialyltransferases and sialidases seem to be involved in the phenomenon of aberrant sialylation in tumor cells. The genetic (stable overexpression sialyltransferase I SAT-I or GM3 synthase) or pharmacological (selective pressure by N-(4-hydroxyphenyl)retinamide)) manipulation of A2780 human ovarian carcinoma cells allowed us to obtain monoclonal cells characterized by higher GM3 synthase activity respect to wild type cells (3-5). High GM3 synthase expression resulted in 1) elevated ganglioside levels, 2) reduced in vitro cell motility and increased adhesion to fibronectin, 3) enhanced expression of the membrane adaptor protein caveolin-1, an integral membrane protein playing multiple roles as negative regulator in the progression of several types of human tumors (6,7). Administration of exogenous gangliosides was able to strongly reduce in vitro cell motility and to increase cell adhesive ability to fibronectin in wild type cells, which