Leidgens, Verena and Proske, Judith and Rauer, Lisa and Moeckel, Sylvia and Renner, Kathrin and Bogdahn, Ulrich and Riemenschneider, Markus J. and Proescholdt, Martin and Vollmann-Zwerenz, Arabel and Hau, Peter and Seliger, Corinna (2017) Stattic and metformin inhibit brain tumor initiating cells by reducing STAT3-phosphorylation. ONCOTARGET, 8 (5). pp. 8250-8263. ISSN 1949-2553,
Full text not available from this repository. (Request a copy)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.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | CANCER STEM-CELLS; HEPATIC INSULIN-RESISTANCE; ACTIVATED PROTEIN-KINASE; HUMAN GLIOBLASTOMA; IN-VITRO; SIGNALING PATHWAYS; BREAST-CANCER; GROWTH; AMPK; TRANSFORMATION; glioma; BTIC; STAT3; Stattic; metformin |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Neurologie |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 14 Dec 2018 13:01 |
| Last Modified: | 27 Feb 2019 07:45 |
| URI: | https://pred.uni-regensburg.de/id/eprint/532 |
Actions (login required)
 |
View Item |
