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Journal of Experimental & Clinical Cancer Research

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Open Access 01-12-2021 | Glioblastoma | Research

Downregulated CLIP3 induces radioresistance by enhancing stemness and glycolytic flux in glioblastoma

Authors: Hyunkoo Kang, Sungmin Lee, Kyeongmin Kim, Jaewan Jeon, Seok-Gu Kang, HyeSook Youn, Hae Yu Kim, BuHyun Youn

Published in: Journal of Experimental & Clinical Cancer Research | Issue 1/2021

Abstract

Background

Glioblastoma Multiforme (GBM) is a malignant primary brain tumor in which the standard treatment, ionizing radiation (IR), achieves a median survival of about 15 months. GBM harbors glioblastoma stem-like cells (GSCs), which play a crucial role in therapeutic resistance and recurrence.

Methods

Patient-derived GSCs, GBM cell lines, intracranial GBM xenografts, and GBM sections were used to measure mRNA and protein expression and determine the related molecular mechanisms by qRT-PCR, immunoblot, immunoprecipitation, immunofluorescence, OCR, ECAR, live-cell imaging, and immunohistochemistry. Orthotopic GBM xenograft models were applied to investigate tumor inhibitory effects of glimepiride combined with radiotherapy.

Results

We report that GSCs that survive standard treatment radiation upregulate Speedy/RINGO cell cycle regulator family member A (Spy1) and downregulate CAP-Gly domain containing linker protein 3 (CLIP3, also known as CLIPR-59). We discovered that Spy1 activation and CLIP3 inhibition coordinately shift GBM cell glucose metabolism to favor glycolysis via two cellular processes: transcriptional regulation of CLIP3 and facilitating Glucose transporter 3 (GLUT3) trafficking to cellular membranes in GBM cells. Importantly, in combination with IR, glimepiride, an FDA-approved medication used to treat type 2 diabetes mellitus, disrupts GSCs maintenance and suppresses glycolytic activity by restoring CLIP3 function. In addition, combining radiotherapy and glimepiride significantly reduced GBM growth and improved survival in a GBM orthotopic xenograft mouse model.

Conclusions

Our data suggest that radioresistant GBM cells exhibit enhanced stemness and glycolytic activity mediated by the Spy1-CLIP3 axis. Thus, glimepiride could be an attractive strategy for overcoming radioresistance and recurrence by rescuing CLIP3 expression.

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Title: Downregulated CLIP3 induces radioresistance by enhancing stemness and glycolytic flux in glioblastoma
Authors: Hyunkoo Kang
Sungmin Lee
Kyeongmin Kim
Jaewan Jeon
Seok-Gu Kang
HyeSook Youn
Hae Yu Kim
BuHyun Youn
Publication date: 01-12-2021
Publisher: BioMed Central
Keywords: Glioblastoma
Glimepiride
Ionizing Radiation
Glioblastoma
Glioblastoma
Published in: Journal of Experimental & Clinical Cancer Research / Issue 1/2021
Electronic ISSN: 1756-9966
DOI: https://doi.org/10.1186/s13046-021-02077-4

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