108 110

Cited 0 times in

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 
Citation
 JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH, Vol.40(1) : 282, 2021-09 
Journal Title
JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH
ISSN
 0392-9078 
Issue Date
2021-09
Keywords
CLIP3 ; Glimepiride ; Glioblastoma ; Glioblastoma stem-like cells ; Radioresistance
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.
Files in This Item:
T202104096.pdf Download
DOI
10.1186/s13046-021-02077-4
Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Neurosurgery (신경외과학교실) > 1. Journal Papers
Yonsei Authors
Kang, Seok Gu(강석구) ORCID logo https://orcid.org/0000-0001-5676-2037
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/185429
사서에게 알리기
  feedback

qrcode

Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.

Browse

Links