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Tumor-initiating cells contained within the aggressive brain tumor glioma (glioma stem cells, GSCs) promote radioresistance and disease recurrence. However, mechanisms of resistance are not well understood. Herein, we show that the proteome-level regulation occurring upon radiation treatment of several patient-derived GSC lines predicts their resistance status, whereas glioma transcriptional subtypes do not. We identify a mechanism of radioresistance mediated by the transfer of the metabolic enzyme NAMPT to radiosensitive cells through microvesicles (NAMPT-high MVs) shed by resistant GSCs. NAMPT-high MVs rescue the proliferation of radiosensitive GSCs and fibroblasts upon irradiation, and upon treatment with a radiomimetic drug or low serum, and increase intracellular NAD(H) levels. Finally, we show that the presence of NAMPT within the MVs and its enzymatic activity in recipient cells are necessary to mediate these effects. Collectively, we demonstrate that the proteome of GSCs provides unique information as it predicts the ability of glioma to resist radiation treatment. Furthermore, we establish NAMPT transfer via MVs as a mechanism for rescuing the proliferation of radiosensitive cells upon irradiation.
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Pharmacological Inhibition of REST in Glioblastoma
Introduction: RE1-silencing transcription factor (REST) silences neuronal differentiation genes. Its overexpression in an aggressive subset of gliomas is believed to support the enhanced tumor-initiating and self-renewal capacities of glioblastoma cancer stem cells (GSCs). Therefore, REST knockdown is hypothesized to inhibit tumor growth and recurrence. Because REST, as a large protein, is difficult to target directly with small molecules, our study focuses on knocking down REST by inhibiting one of its regulatory enzymes, small C-terminal domain phosphatase 1 (SCP1). Dephosphorylation of REST by SCP1 protects the former from degradation; consequently, SCP1 inhibition with an experimental drug, T62, is expected to reduce REST protein levels. This REST knockdown is hypothesized to induce the expression of neuronal differentiation genes, thereby forcing differentiation of GSCs and making them more vulnerable to standard treatments. We begin our study by validating patient-derived GSC lines and subsequently testing the efficacy of T62 drug in these cells. Our work supports an effort to understand various molecular pathologies of GBM and its intrinsic GSCs in order to develop novel therapeutic strategies.
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- Award ID(s):
- 1757885
- PAR ID:
- 10138564
- Date Published:
- Journal Name:
- 2019 BMES Conference Proceedings - REU Abstract Accepted Poster
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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