Abstract
The elucidation of mechanisms involved in resistance to therapies is essential to improve the survival of patients with malignant gliomas. A major feature possessed by glioma cells that may aid their ability to survive therapy and reconstitute tumors is the capacity for self-renewal. We show here that glioma stem cells (GSCs) express low levels of MKP1, a dual-specificity phosphatase, which acts as a negative inhibitor of JNK, ERK1/2, and p38 MAPK, while induction of high levels of MKP1 expression are associated with differentiation of GSC. Notably, we find that high levels of MKP1 correlate with a subset of glioblastoma patients with better prognosis and overall increased survival. Gain of expression studies demonstrated that elevated MKP1 impairs self-renewal and induces differentiation of GSCs while reducing tumorigenesis in vivo. Moreover, we identified that MKP1 is epigenetically regulated and that it mediates the anti-tumor activity of histone deacetylase inhibitors (HDACIs) alone or in combination with temozolomide. In summary, this study identifies MKP1 as a key modulator of the interplay between GSC self-renewal and differentiation and provides evidence that the activation of MKP1, through epigenetic regulation, might be a novel therapeutic strategy to overcome therapy resistance in glioblastoma.
Highlights
The elucidation of mechanisms involved in resistance to therapies is essential to improve the survival of patients with malignant gliomas
We moved to patient-derived glioma stem cells (GSCs) observing that four different cultures, two grown as adherent lines (GNS166, GNS179) and another two as oncospheres (GB2 and GB1) expressed even lower MKP1 messenger RNA levels than conventional glioma cell lines and healthy brain tissue (Fig. 1a)
Median overall survival of patients with high levels of MKP1 was 14 and 18 months in cohort 1 and 2, compared to 9 and 6 with low MKP1, respectively. These results show that MKP1 messenger RNA (mRNA) expression is generally low in tumor samples, lower levels are associated with advanced glioma grade, but these low levels of MKP1 correlate with poor overall patient survival underlining the impact of MKP1 expression as an independent glioblastoma prognostic marker
Summary
The elucidation of mechanisms involved in resistance to therapies is essential to improve the survival of patients with malignant gliomas. A major feature possessed by glioma cells that may aid their ability to survive therapy and reconstitute tumors is the capacity for self-renewal. This study identifies MKP1 as a key modulator of the interplay between GSC self-renewal and differentiation and provides evidence that the activation of MKP1, through epigenetic regulation, might be a novel therapeutic strategy to overcome therapy resistance in glioblastoma. It has been found that the activation of MAPKs is necessary for GSCs self-renewal activity, the ability to initiate tumors and radioresistance[14,15,16,17], leading to the evidence that GSCs maintenance via MAPKs is a major step in the progression and therapy resistance of glioblastoma
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