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

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.

• Authors: Hyunkoo Kang, Sungmin Lee, Kyeongmin Kim, Jaewan Jeon, Seok-Gu Kang, HyeSook Youn, Hae Yu Kim, BuHyun Youn
• Journal: Journal of experimental & clinical cancer research : CR (J Exp Clin Cancer Res) Vol. 40 Issue 1 Pg. 282 (Sep 06 2021) ISSN: 1756-9966 [Electronic] England
• PMID: 34488821 (Publication Type: Journal Article)
• Copyright: © 2021. The Author(s).

Chemical References

• CLIP3 protein, human
• Microtubule-Associated Proteins

Topics

• Animals
• Brain Neoplasms (genetics, metabolism, pathology, radiotherapy)
• Cell Line, Tumor
• Disease Models, Animal
• Down-Regulation
• Glioblastoma (genetics, metabolism, pathology, radiotherapy)
• Glycolysis
• Humans
• Male
• Mice
• Mice, Nude
• Microtubule-Associated Proteins (genetics, metabolism)
• Neoplastic Stem Cells (metabolism, pathology, radiation effects)
• Radiation Tolerance
• Xenograft Model Antitumor Assays