Oligosaccharyltransferase Inhibition Reduces Receptor Tyrosine Kinase Activation and Enhances Glioma Radiosensitivity.

Abstract

PURPOSE:

Parallel signaling reduces the effects of receptor tyrosine kinase (RTK)-targeted therapies in glioma. We hypothesized that inhibition of protein N-linked glycosylation, an endoplasmic reticulum co- and posttranslational modification crucial for RTK maturation and activation, could provide a new therapeutic approach for glioma radiosensitization.Experimental Design: We investigated the effects of a small-molecule inhibitor of the oligosaccharyltransferase (NGI-1) on EGFR family receptors, MET, PDGFR, and FGFR1. The influence of glycosylation state on tumor cell radiosensitivity, chemotherapy-induced cell toxicity, DNA damage, and cell-cycle arrest were determined and correlated with glioma cell receptor expression profiles. The effects of NGI-1 on xenograft tumor growth were tested using a nanoparticle formulation validated by in vivo molecular imaging. A mechanistic role for RTK signaling was evaluated through the expression of a glycosylation-independent CD8-EGFR chimera.

RESULTS:

NGI-1 reduced glycosylation, protein levels, and activation of most RTKs. NGI-1 also enhanced the radiosensitivity and cytotoxic effects of chemotherapy in those glioma cells with elevated ErbB family activation, but not in cells without high levels of RTK activation. NGI-1 radiosensitization was associated with increases in both DNA damage and G1 cell-cycle arrest. Combined treatment of glioma xenografts with fractionated radiotherapy and NGI-1 significantly reduced tumor growth compared with controls. Expression of the CD8-EGFR eliminated the effects of NGI-1 on G1 arrest, DNA damage, and cellular radiosensitivity, identifying RTK inhibition as the principal mechanism for the NGI-1 effect.

CONCLUSIONS:

This study suggests that oligosaccharyltransferase inhibition with NGI-1 is a novel approach to radiosensitize malignant gliomas with enhanced RTK signaling.See related commentary by Wahl and Lawrence, p. 455.

• Authors: Marta Baro, Cecilia Lopez Sambrooks, Amanda Quijano, W Mark Saltzman, Joseph Contessa
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 25 Issue 2 Pg. 784-795 (01 15 2019) ISSN: 1557-3265 [Electronic] United States
• PMID: 29967251 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: ©2018 American Association for Cancer Research.

Chemical References

• Antineoplastic Agents
• Membrane Proteins
• Radiation-Sensitizing Agents
• Hexosyltransferases
• dolichyl-diphosphooligosaccharide - protein glycotransferase
• ErbB Receptors
• Receptor Protein-Tyrosine Kinases

Topics

• Animals
• Antineoplastic Agents (administration & dosage, pharmacology)
• Cell Cycle Checkpoints (drug effects, radiation effects)
• Cell Line, Tumor
• Cell Survival (drug effects, radiation effects)
• Disease Models, Animal
• Dose-Response Relationship, Drug
• Dose-Response Relationship, Radiation
• ErbB Receptors (metabolism)
• Glioma (metabolism, pathology, radiotherapy)
• Hexosyltransferases (antagonists & inhibitors)
• Humans
• Membrane Proteins (antagonists & inhibitors)
• Mice
• Radiation Tolerance (genetics)
• Radiation-Sensitizing Agents (administration & dosage, pharmacology)
• Receptor Protein-Tyrosine Kinases (metabolism)
• Signal Transduction (drug effects)
• Xenograft Model Antitumor Assays