Irradiation of pediatric glioblastoma cells promotes radioresistance and enhances glioma malignancyviagenome-wide transcriptome changes

Abstract

Pediatric glioblastoma (GBM) is a relatively rare brain tumor in children that has a dismal prognosis. Surgery followed by radiotherapy is the main treatment protocol used for older patients. The benefit of adjuvant chemotherapy is still limited due to a poor understanding of the underlying molecular and genetic changes that occur with irradiation of the tumor. In this study, we performed total RNA sequencing on an established stable radioresistant pediatric GBM cell line to identify mRNA expression changes following radiation. The expression of many genes was altered in the radioresistant pediatric GBM model. These genes have never before been reported to be associated with the development of radioresistant GBM. In addition to exhibiting an accelerated growth rate, radioresistant GBM cells also have overexpression of the DNA synthesis-rate-limiting enzyme ribonucleotide reductase, and pro-cathepsin B. These newly identified genes should be concertedly studied to better understand their role in pediatric GBM recurrence and progression after radiation. It was observed that the changes in multiple biological pathways protected GBM cells against radiation and transformed them to a more malignant form. These changes emphasize the importance of developing a treatment regimen that consists of a multiple-agent cocktail that acts on multiple implicated pathways to effectively target irradiated pediatric GBM. An alternative to radiation or a novel therapy that targets differentially expressed genes, such as metalloproteases, growth factors, and oncogenes and aim to minimize oncogenic changes following radiation is necessary to improve recurrent GBM survival.

Hypoxia, metabolism, and the circadian clock: new links to overcome radiation resistance in high-grade gliomas

“…Secondly, the post-radiotherapy upregulation of genes controlling DNA repair, cell proliferation and anti-apoptosis is also believed to play an important role in radiotherapy-induced radioresistance, particularly when a sub-lethal dose of radiotherapy was cumulatively delivered [45]. This has been frequently reported by studies investigating adult glioblastomas and a very recent report has also confirmed the similar findings in pHGGs [46]. Last but not least, radiotherapy-induced generation and enrichment of cancer stem cells is also a major obstacle for maintaining the efficacy of radiotherapy to eradicate cancer cells.…”

<p>Role of Hippo/YAP signaling in irradiation-induced glioma cell apoptosis</p>

“…13 It is well documented that pathways induced tumor cell excessive proliferation and defective apoptosis account for the major mechanisms of radioresistance in cancer cells. [14][15][16] Therefore, here, we explored the roles of Hippo/YAP signaling in glioma cell proliferation and apoptosis under irradiation exposure. We report a new effective manner that downregulation of YAP can significantly enhance the radiosensitivity of glioma cells.…”

Therapeutic Targeting of Cancer Stem Cells in Human Glioblastoma by Manipulating the Renin-Angiotensin System

“…Caffeine was found to suppress proliferation of GB cell lines, and is associated with decreased activity of cathepsin B and up-regulation of tissue inhibitor of metalloproteinase-1 via the MAPK signaling pathway [86]. RNA sequencing of a radio-resistant pediatric GB cell line following radiation revealed the over-expression of pro-cathepsin B, implicating the potential for alternative therapies that target metalloproteinases or cathepsin B [87]. Expression of cathepsin B and cathepsin D was demonstrated in OCT4+ and SALL4+ CSCs in IDH-wildtype GB [88] (Figure 2).…”