Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive soft tissue sarcomas that occur either sporadically or in patients with Neurofibromatosis type I. Surgery is the main stay of treatment, however, due to the invasive growth, propensity to metastasis, limited sensitivity to chemotherapy and radiation therapy, 5-year survival rates is only 20%-50%. Recent studies have identified several altered intracellular signal transduction cascades and deregulated expression of kinase receptors in MPNSTs, posing the possibility of personalized, targeted therapeutics for these diseases. Kinase receptors depend on the glycosylation for stabilization, maturation, transport onto the cell surface, phosphorylation and activation. Aberrant glycosylation to stabilize the expression of kinase receptors on the cell surface is associated with many cancers. The appropriate and accurate modification of glycans to proteins mainly depends on the action of highly specific and precisely located enzymes known as glycosyltransferases and glycosidases in different tissues and cells. In this report, we found that glycoproteins were highly expressed in MPNST cell lines compared with normal Schwann cells (NSC). We used the Human Glycosylation PCR Array to profile the expression of 84 key genes encoding enzymes that regulate protein glycosylation. We did not identify any change in glycosidase mRNA expression levels, whereas multiple glycosyltransferases (B4GALT5, FUT8, MGAT3, MGAT4A, MGAT5, MGAT5B, GALNT13, GALNT14, POMT1, ST8SIA2) were overexpressed in different MPNST cell lines. This is especially true for MGAT5B, a glycosyltransferase that promotes N-linked or O-linked protein glycosylation, which was highly expressed in all MPNST cell lines, many MPNST clinical specimens, as well as colon and pancreatic cancer cell lines with K-ras mutations. Exogenous expression of K-ras (G12V) significantly upregulated MGAT5B expression to promote glycosylation of several tyrosine kinase receptors, whereas knockdown of MGAT5B significantly inhibited the glycosylation and phosphorylation of these kinase receptors. Moreover, we found AKT interacted with and phosphorylated Ser192 in MGAT5B to promote MGAT5B transport from the cytoplasm to the Golgi apparatus. Mutated MGAT5BS192A protein stayed in the cytoplasm significantly attenuated experimental lung tumor metastasis in vivo. Furthermore treatment of MPNST cells with the PI3K inhibitor Ly294002 inhibited MGAT5B glycosyltransferase activity to attenuate glycosylation and phosphorylation of tyrosine kinase receptors. Taken together, these data suggest that RAS-mediated MGAT5B expression plays a critical role in promoting glycosylation of many kinase receptors. Targeting MGAT5B-mediated protein glycosylation may open a new therapeutic window for the treatment of MPNSTs and RAS-related malignancies.

Citation Format: Quansheng Zhu, Hui Shang, Yechun Song, Yi Zhang, Raphael Pollock, Steven Hsesheng Lin. MGAT5B expression in malignant peripheral nerve sheath tumors and RAS-mutated tumors promote maturation of tyrosine kinase receptors through a PI3K/AKT/MGAT5B mechanism. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2770. doi:10.1158/1538-7445.AM2014-2770