Abstract 4577: Targeting N-glycosylation of tyrosine kinase receptors for preventing tumorigenesis and malignant transformation of neurofibromatosis type I

Abstract

Abstract Neurofibromatosis type I (NF1) is a dominantly inherited disease affecting 1 in every 2,500 to 3,000 individuals, representing the most common familial cancer predisposition syndrome. The hallmark of clinical manifestation of NF1 is the development of multiple neurofibromas, which are highly heterotypic benign tumors of peripheral nerve sheath mainly composed of immature Schwann cells, fibroblasts, perineurial and inflammatory matrix. NF1 patients are also at high risk for the development of certain maligancies such as pheochromocytomas, childhood myeloid leukemias, neuroblastomas, rhabdomyosarcomas, and malignant peripheral nerve sheath tumors (MPNSTs). Because of the potential involvement of underlying nerves and blood vessels, surgical removal of tumors is not always an option. Once progressing to MPNSTs, although the resection is possible, most patients will eventually relapse locally or systemically. There is no effective treatment for NF1, nor effective approaches for predicting or preventing the occurrence of devastating complications. Thus, to develop agents for preventing or reversing the tumorigenesis and malignant transformation of NF1 are critically needed. In this report, we found HGF, c-MET, EGF and EGFR are aberrantly expressed in clinical specimens of neurofibromas and MPNSTs with NF and that autocrine and/or paracrine HGF/c-MET and EGF/EGFR loops promote MPSNT cell migration and invasion in vitro (Fig1). We also found that the loss of Nf1 in neurofibromas and MPNSTs results in hyperactive of Ras (Fig2). Compared with normal Schwann cells, MPNST cells express more N-glycoproteins and display different N-glycoprotein signatures (Fig3). In order to confirm our hypothesis, we treated cells with Tunicamycin, or 2-DG (N-glycosylation inhibitors) respectively in variable doses for different time. We found that both Tunicamycin and 2-DG inhibited the proliferation and promoted apoptosis of MPNST cell lines but had no effect on normal human Schwann cells (Fig4); inhibited the glycosylation and phosphorylation of EGFR and c-MET and impaired receptor-mediated MEK-ERK1/2 and PI3K-AKT signaling in a dose-dependent manner (Fig5). Moreover, 2-DG inhibited the maturation of c-MET as demonstrated by the intact premature chain, failing to cleave into one mature α-chain and another mature α-chain. In addition, 2-DG inhibited the translocation of the receptors from the cytoplasm onto the cell surface and retained receptors in the ER and Golgi apparatus (Fig6). To date, 2-DG inhibition of N-glycosylation and phosphorylation of tyrosine kinase receptors has not been reported. These novel findings prompted us to explore whether 2-DG disrupts Ras-directed N-glycosylation of tyrosine receptors in Schwann cell progenitors and tumor cells and to evaluate its roles in preventing the tumorigenesis and malignant transformation of NF1. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4577. doi:1538-7445.AM2012-4577