Abstract
Glioblastoma (GBM) is the most common and malignant type of primary brain tumor and associated with a devastating prognosis. Signal transducer and activator of transcription number 3 (STAT3) is an important pathogenic factor in GBM and can be specifically inhibited with Stattic. Metformin inhibits GBM cell proliferation and migration. Evidence from other tumor models suggests that metformin inhibits STAT3, but there is no specific data on brain tumor initiating cells (BTICs).We explored proliferation and migration of 7 BTICs and their differentiated counterparts (TCs) after treatment with Stattic, metformin or the combination thereof. Invasion was measured in situ on organotypic brain slice cultures. Protein expression of phosphorylated and total STAT3, as well as AMPK and mTOR signaling were explored using Western blot. To determine functional relevance of STAT3 inhibition by Stattic and metformin, we performed a stable knock-in of STAT3 in selected BTICs.Inhibition of STAT3 with Stattic reduced proliferation in all BTICs, but only in 4 out of 7 TCs. Migration and invasion were equally inhibited in BTICs and TCs. Treatment with metformin reduced STAT3-phosphorylation in all investigated BTICs and TCs. Combined treatment with Stattic and metformin led to significant additive effects on BTIC proliferation, but not migration or invasion. No additive effects on TCs could be detected. Stable STAT3 knock-in partly attenuated the effects of Stattic and metformin on BTICs.In conclusion, metformin was found to inhibit STAT3-phosphorylation in BTICs and TCs. Combined specific and unspecific inhibition of STAT3 might represent a promising new strategy in the treatment of glioblastoma.
Highlights
High-grade gliomas, especially glioblastomas (GBM), are highly complex and heterogeneous primary brain tumors, accounting for about 30% of all tumors of the central nervous system [1]
In addition to specific STAT3 inhibition with Stattic, we investigated whether metformin inhibits STAT3-phosphorylation in brain tumor initiating cells (BTICs) and whether additive effects can be achieved by combining Stattic with the approved and clinically welltolerated anti-diabetic drug metformin
Combined treatment with Stattic and metformin increases functional effects Based on the influence of metformin on STAT3phosphorylation we investigated the effects of combined treatment with Stattic and metformin on proliferation (Figure 6) and migration (Figure 7) of BTICs and their differentiated counterparts (TCs)
Summary
High-grade gliomas, especially glioblastomas (GBM), are highly complex and heterogeneous primary brain tumors, accounting for about 30% of all tumors of the central nervous system [1]. Persistent activation of STAT3 (signal transducer and activator of transcription number 3) has been detected in many cancers [7], including gliomas, and is correlated www.impactjournals.com/oncotarget with poor survival [8]. This was confirmed by correlation of strong expression of STAT3 phosphorylated at Y705 in GBM specimens with a more aggressive phenotype and shorter overall survival [9]. The STAT inhibitor Stattic [12] was shown to selectively inhibit STAT3 [13] It is still unclear whether Stattic binds directly to the phosphorylation site at Y705 or if it acts by altering the conformation of the SH2 domain, because it binds to Cys687 on the opposite side of the phosphopeptide binding face [13]
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