Stattic and metformin inhibit brain tumor initiating cells by reducing STAT3-phosphorylation

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.

Use of metformin and outcome of patients with newly diagnosed glioblastoma: Pooled analysis

“…Our results are in contrast to several experimental preclinical studies suggesting inhibitory effects of metformin on glioma cells . One major drawback of those studies may however be that metformin doses used in cell culture are frequently by far higher than the concentrations measured in the brain of diabetic patients.…”

“…17 Our results are in contrast to several experimental preclinical studies suggesting inhibitory effects of metformin on glioma cells. [6][7][8][9][10][11][12][27][28][29] One major drawback of those studies may however be that metformin doses used in cell culture are frequently by far higher than the concentrations measured in the brain of diabetic patients. In vitro studies often used metformin doses in the millimolar (10 −3 , mM) range, 6,7,[9][10][11][12]28,29 whereas metformin doses in the brain of diabetic patients have been measured in the micromolar (10 −6 , μM) range.…”

Ribosomal protein S6 promotes stem‐like characters in glioma cells

“…Part of the reason for its chemoradioresistance is the presence of a small population of cells with stem cell‐like characters, so called GBM stem cells (GSC) in GBM 4 . GSCs are generally present in a special microenvironment, the GSC niche, and retain their potential for self‐renewal, chemoradioresistance, and tumorigenicity 5 . Despite different types of GSC niches, such as perivascular, perinecrotic, and border niches, 6,7 the mechanisms underlying the promotion of stem cell‐like features in glioma cells by these niches remain largely unknown.…”

Blocking epithelial-to-mesenchymal transition in glioblastoma with a sextet of repurposed drugs: the EIS regimen

“…Leidgens et al found glioma cell exposure to metformin resulted in decreased glioma cell proliferation and increased AMPK activation, as found by others, but also inhibition phosphorylation of STAT3 in [ 255 ].…”