Abstract
Resistance to therapeutic use of retinoids in glioma has been observed for over 20 years; however, the exact mechanism of resistance remains unknown. To understand retinoic acid resistance in glioma, we studied the turnover mechanism of retinoid receptor proteins in neural stem cells and glioma stem-like cells. Here, we show that in normal neural stem cells, proteasomal degradation of retinoid receptors involves sumoylation, ubiquitination and recognition by the valosin-containing protein (VCP/p97/Cdc48). We find that Sumo1 modification has a dual role to stabilize the retinoid receptor from unwanted degradation and signal additional modification via ubiquitination. Subsequently, the modified receptor binds to the VCP chaperone and both proteins are degraded by the proteasome. Additionally, we reveal that all trans retinoic acid (ATRA) induces VCP expression, creating a positive feedback loop that enhances degradation. In contrast, the pathway is impaired in the glioma stem-like cells resulting in the accumulation of sumoylated and high molecular weight forms of retinoid receptors that lack transcriptional activity and fail to be recognized by the proteasome. Moreover, modified receptor accumulation occurs before ATRA treatment; therefore, the transcritptional defect in glioma is due to a block in the proteasomal degradation pathway that occurs after the sumo modification step.
Highlights
Resistance to therapeutic use of retinoids in glioma has been observed for over 20 years; the exact mechanism of resistance remains unknown
Sumoylation of RARA occurs in normal murine neural stem cells as part of proteasomal degradation pathway, this pathway is disrupted in glioma stem-like cells
To confirm that the down regulation of RARA was due to protein degradation by the proteasomal pathway, the murine neural stem cells (MNSC) e14 cell line was treated with MG132, a chemical inhibitor of the proteasome
Summary
Resistance to therapeutic use of retinoids in glioma has been observed for over 20 years; the exact mechanism of resistance remains unknown. We show that in normal neural stem cells, proteasomal degradation of retinoid receptors involves sumoylation, ubiquitination and recognition by the valosin-containing protein (VCP/p97/Cdc[48]). The pathway is impaired in the glioma stem-like cells resulting in the accumulation of sumoylated and high molecular weight forms of retinoid receptors that lack transcriptional activity and fail to be recognized by the proteasome. We reveal that the mechanism of proteasomal degradation in retinoid receptors in normal neural stem cells involves sumoylation, ubiquitination and recognition by valosin-containing protein (VCP/p97/Cdc[48]). The degradation pathway in glioma stem-like cells is impaired resulting in the accumulation of high molecular weight forms of the receptor that lack transcriptional activity and fail to be recognized by the proteasome. Our studies suggest that the use of combinatory therapies that target retinoid receptors and induce proteasomal degradation of the receptors to ensure protein turnover may provide a more effective therapeutic approach
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