Ras-Directed N-Glycoproteins are Novel Early Biomarkers for Tumorigenesis and Malignant Transformation, and Therapeutic Targets of Neurofibromatosis Type I

Abstract

Abstract : Neurofibromatosis type I (NF1) is a dominantly inherited disease affecting 3,000 individuals. The hall marker of NF1 is the development of neurofibromas and about 10% of neurofibroma will develop malignant peripheral nerve sheath tumors (MPNSTs). .In this report, we found AXL, c-MET and EGFR are aberrantly expressed in clinical specimens of neurofibromas and MPNSTs, and MPNST cells express high level of glycoproteins. We also found hyperactive Ras unregulated the expression of MGAT5B, one of the glycosyltransferases, to mediate the glycosylation and phosphorylation of kinase receptors in all MPNST cell lines and clinical specimens, and MGT5B shRNA knockdown significantly inhibited the glycosylation and phosphorylation of kinase receptors. We treated cells with 2-Deoxy-D-Glucose (2-DG), a potential glycosylation inhibitor, and found 2-DG inhibited the glycosylation and phosphorylation of AXL, EGFR, and c-MET and impaired receptor-mediated MEKERK1/ 2 and PI3K-AKT signaling in a dose-dependent manner, and inhibited the translocation of receptors from the cytoplasm to the cell surface and retained receptors in the ER and Golgi apparatus, but had no effect on normal human Schwann cells. Furthermore, we found that 2-DG inhibited the tumor development in NF1+/-;p53+/- mice. These novel findings suggest MGAT5B is a novel therapeutic target of NF1 to prevent the tumorigenesis and malignant transformation.