Role of Globotriaosylceramide in Physiology and Pathology

Abstract

At first glance, the biological function of globoside (Gb) clusters appears to be that of glycosphingolipid (GSL) receptors for bacterial toxins that mediate host-pathogen interaction. Indeed, certain bacterial toxin families have been evolutionarily arranged so that they can enter eukaryotic cells through GSL receptors. A closer look reveals this molecular arrangement allocated on a variety of eukaryotic cell membranes, with its role revolving around physiological regulation and pathological processes. What makes Gb such a ubiquitous functional arrangement? Perhaps its peculiarity is underpinned by the molecular structure itself, the nature of Gb-bound ligands, or the intracellular trafficking unleashed by those ligands. Moreover, Gb biological conspicuousness may not lie on intrinsic properties or on its enzymatic synthesis/degradation pathways. The present review traverses these biological aspects, focusing mainly on globotriaosylceramide (Gb3), a GSL molecule present in cell membranes of distinct cell types, and proposes a wrap-up discussion with a phylogenetic view and the physiological and pathological functional alternatives.

Novel lectin-based chimeric antigen receptors target Gb3-positive tumour cells

“…We aimed herein to target Gb3 in tumours with genetically engineered T cells. Previous studies have demonstrated that Gb3 is overexpressed in leukaemia, colorectal, breast, lung, pancreatic, ovarian, and testicular cancer, among other malignancies [ 53 , 54 ]. Recently, enhanced expression of Gb3 has been described as correlating with the development of metastasis in colon cancer [ 33 , 42 ] and multi-drug resistance in breast [ 55 ], lung, ovarian [ 56 ] and myeloid leukaemias [ 57 ].…”

“…Although tumour imaging studies in mice with StxB did not show extensive off-targeting [ 93 – 95 , 121 ], still there is a reasonable risk of targeting normal tissue in which Gb3 is also expressed, e.g. kidney [ 122 ], nervous system [ 123 ], liver or intestine [ 53 , 124 ]. The clinical translation of these findings remains to be done; our study is designed as a proof-of-concept, and it has herewith demonstrated the feasibility of targeting cancer cells by using novel and innovative lectin-CAR constructs.…”

The choanoflagellate pore-forming lectin SaroL-1 punches holes in cancer cells by targeting the tumor-related glycosphingolipid Gb3

“…We could also demonstrate that SaroL-1 is not active on Gb3- depleted cancer cells. As recently reviewed 67 , Gb3 is expressed in a limited number of human organs (lung, kidney, lymph node and CNS), so SaroL-1 might not be specific solely towards cancer cells, limiting possible applications in targeted treatments. Nonetheless, the Gb3-targeting verotoxin proved to be selective in the elimination of human tumor xenografts in mice 68 , 69 .…”

Clickable Shiga Toxin B Subunit for Drug Delivery in Cancer Therapy

“…When bound to nonlipid raft Gb3, STxB follows the degradative pathway to lysosomes. , This fraction of lysosomal STxB offers an opportunity for the targeted intracellular delivery of drugs such as DBCO-PEG4-Val-Cit-PAB-MMAE. The delivery of antitumoral drugs by STxB was previously tested on Gb3-expressing tumor cell lines derived from colorectal, lung, or breast carcinomas. − These human cell lines are an effective model for assessing the ability of STxB to deliver various treatments in vitro .…”