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Downregulated CLIP3 induces radioresistance by enhancing stemness and glycolytic flux in glioblastoma
- Source :
- Journal of Experimental & Clinical Cancer Research : CR, Journal of Experimental & Clinical Cancer Research, Vol 40, Iss 1, Pp 1-18 (2021)
- Publication Year :
- 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.
- Subjects :
- Male
Cancer Research
Cell
Down-Regulation
Mice, Nude
Radiation Tolerance
Mice
Downregulation and upregulation
Radioresistance
Cell Line, Tumor
medicine
Transcriptional regulation
Animals
Humans
RC254-282
biology
Chemistry
Brain Neoplasms
Research
Glimepiride
Glucose transporter
Neoplasms. Tumors. Oncology. Including cancer and carcinogens
Xenograft Model Antitumor Assays
Disease Models, Animal
medicine.anatomical_structure
Oncology
Glioblastoma stem-like cells
Apoptosis
Cell culture
Cancer research
biology.protein
Neoplastic Stem Cells
CLIP3
Glioblastoma
Glycolysis
Microtubule-Associated Proteins
GLUT3
Subjects
Details
- ISSN :
- 17569966
- Volume :
- 40
- Issue :
- 1
- Database :
- OpenAIRE
- Journal :
- Journal of experimentalclinical cancer research : CR
- Accession number :
- edsair.doi.dedup.....3471d5a64b794c75cbd133c6bace8c32