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- 2019년 02월호
[Clin Cancer Res.] Oligosaccharyltransferase 억제가 Receptor Tyrosine Kinase 활성화를 억제하고 교모종의 방사선감수성을 증가시킴
Oligosaccharyltransferase Inhibition Reduces Receptor Tyrosine Kinase Activation and Enhances Glioma Radiosensitivity.Yale University Medical School / Joseph Contessa*
- 출처
- Clin Cancer Res.
- 등재일
- 2019 Jan 15
- 저널이슈번호
- 25(2):784-795. doi: 10.1158/1078-0432.CCR-18-0792. Epub 2018 Jul 2.
- 내용
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.
Author informationBaro M1, Lopez Sambrooks C1, Quijano A2, Saltzman WM2, Contessa J3,4.
1
Department of Therapeutic Radiology, Yale University, New Haven, Connecticut.
2
Department of Biomedical Engineering, Yale University, New Haven, Connecticut.
3
Department of Therapeutic Radiology, Yale University, New Haven, Connecticut. joseph.contessa@yale.edu.
4
Department of Pharmacology, Yale University, New Haven, Connecticut.
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