Abstract
Relapse is the main cause of mortality in patients with glioblastoma multiforme (GBM). Treatment options involve surgical resection followed by a combination of radiotheraphy and chemotherapy with temozolomide. Several genes and genetic pathways have been identified to contribute to therapeutic resistance, giving rise to recurrence of the malignancy. In the last decades, glioma stem cells (GSCs) with the capacity of self-renewal have been demonstrated to maintain tumor propagation and treatment resistance. Here, we isolated CD133-positive (CD133+) and CD133-negative (CD133−) cells from glioblastoma U98G and U87MG cell lines. The role of phosphoribosylpyrophosphate synthetase 1 (PRPS1), which catalyzes the first step of the synthesis of nucleotide, in proliferation and apoptosis was investigated. We found that PRPS1 had a remarkable effect on cell proliferation and sphere formation in both CD133+ and CD133− cells. Compared to CD133− cells, CD133+ cells exhibited more significant results in cell apoptosis assay. CD133+ T98G and U87MG cells were used in xenograft mouse model of tumor formation. Interestingly, the mice implanted with PRPS1 knockdown T98G or U87MG stem cells exhibited prolonged survival time and reduced tumor volume. By immunostaining caspase-3 in tumor tissues of these mice, we demonstrated that the apoptotic activities in tumor cells were positively correlated to the survival time but negatively correlated to PRPS1 expression. Our results indicate that PRPS1 plays an important role in proliferation and apoptosis in GSCs and provide new clues for potential PRPS1-targeted therapy in GBM treatment.
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This work was supported by the Natural Science Foundation of China (81401032).
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The protocols approved by the Committee on the Ethics of Animal Experiments of The Second Hospital of Hebei Medical University.
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Li, C., Yan, Z., Cao, X. et al. Phosphoribosylpyrophosphate Synthetase 1 Knockdown Suppresses Tumor Formation of Glioma CD133+ Cells Through Upregulating Cell Apoptosis. J Mol Neurosci 60, 145–156 (2016). https://doi.org/10.1007/s12031-016-0783-y
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DOI: https://doi.org/10.1007/s12031-016-0783-y