Abstract
Human glioblastoma (GBM) is the most common primary malignant brain tumor. A minor subpopulation of cancer cells, known as glioma stem-like cells (GSCs), are thought to play a major role in tumor relapse due to their stem cell-like properties, their high resistance to conventional treatments and their high invasion capacity. We show that ionizing radiation specifically enhances the motility and invasiveness of human GSCs through the stabilization and nuclear accumulation of the hypoxia-inducible factor 1α (HIF1α), which in turn transcriptionally activates the Junction-mediating and regulatory protein (JMY). Finally, JMY accumulates in the cytoplasm where it stimulates GSC migration via its actin nucleation-promoting activity. Targeting JMY could thus open the way to the development of new therapeutic strategies to improve the efficacy of radiotherapy and prevent glioma recurrence.
Highlights
Human glioblastoma (GBM) is the most common primary malignant brain tumor
We show that radiation-induced migration/invasion occurs through the stabilization and nuclear accumulation of the transcription factor hypoxia-inducible factor 1 alpha (HIF1α), which drives the transcription of Junction-mediating and regulatory protein (JMY)[27] that stimulates glioma stem-like cells (GSCs) migration through its actin nucleation-promoting activity
We report that sublethal doses of irradiation enhance the motility and invasiveness of human GSCs through hypoxia-inducible factor 1α (HIF1α) nuclear accumulation that in turn increases the cytoplasmic actin nucleator JMY
Summary
GSCs are thought to play crucial roles in GBM relapse[23,25]. Here, we report that sublethal doses of irradiation enhance the motility and invasiveness of human GSCs through HIF1α nuclear accumulation that in turn increases the cytoplasmic actin nucleator JMY. To our knowledge, our study is the first to show that human GSCs are prone to this radiation effect, and that this is linked to their stemness properties, as radiation did not induce this effect on “differentiated” glioma cells. Our study shows that the key factor linking the radiation-induced enhancement of GSCs to stem-like properties is the fact that GSCs are much more prone than differentiated cells to the activation of HIF1α in response to radiation This may explain why we were able to show that 0.5 Gy enhanced the migration of GSCs, whereas Kim et al have reported that 6 Gy-irradiation in either single or fractioned doses, but not 2 Gy irradiation, was able to induce HIF1α stabilization and stimulate the migration of U87 and U373 glioma c ells[9]. Specific targeting of JMY could provide new therapeutic perspectives to limit radiation-induced migration of GSCs and prevent tumor recurrence following radiotherapy
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