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Metformin inhibits proliferation and migration of glioblastoma cells independently of TGF-?2.

ABSTRACT: To this day, glioblastoma (GBM) remains an incurable brain tumor. Previous research has shown that metformin, an oral anti-diabetic drug, may decrease GBM cell proliferation and migration especially in brain tumor initiating cells (BTICs). As transforming growth factor ? 2 (TGF-?2) has been reported to promote high-grade glioma and is inhibited by metformin in other tumors, we explored whether metformin directly interferes with TGF-?2-signaling. Functional investigation of proliferation and migration of primary BTICs after treatment with metformin+/-TGF-?2 revealed that metformin doses as low as 0.01 mM metformin thrice a day were able to inhibit proliferation of susceptible cell lines, whereas migration was impacted only at higher doses. Known cellular mechanisms of metformin, such as increased lactate secretion, reduced oxygen consumption and activated AMPK-signaling, could be confirmed. However, TGF-?2 and metformin did not act as functional antagonists, but both rather inhibited proliferation and/or migration, if significant effects were present. We did not observe a relevant influence of metformin on TGF-?2 mRNA expression (qRT-PCR), TGF-?2 protein expression (ELISA) or SMAD-signaling (Western blot). Therefore, it seems that metformin does not exert its inhibitory effects on GBM BTIC proliferation and migration by altering TGF-?2-signaling. Nonetheless, as low doses of metformin are able to reduce proliferation of certain GBM cells, further exploration of predictors of BTICs' susceptibility to metformin appears justified.

SUBMITTER: Seliger C

PROVIDER: S-EPMC4957567 | biostudies-literature | 2016 Jul

REPOSITORIES: biostudies-literature

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Metformin inhibits proliferation and migration of glioblastoma cells independently of TGF-β2.

Seliger Corinna C Meyer Anne-Louise AL Renner Kathrin K Leidgens Verena V Moeckel Sylvia S Jachnik Birgit B Dettmer Katja K Tischler Ulrike U Gerthofer Valeria V Rauer Lisa L Uhl Martin M Proescholdt Martin M Bogdahn Ulrich U Riemenschneider Markus J MJ Oefner Peter J PJ Kreutz Marina M Vollmann-Zwerenz Arabel A Hau Peter P

Cell cycle (Georgetown, Tex.) 20160510 13

To this day, glioblastoma (GBM) remains an incurable brain tumor. Previous research has shown that metformin, an oral anti-diabetic drug, may decrease GBM cell proliferation and migration especially in brain tumor initiating cells (BTICs). As transforming growth factor β 2 (TGF-β2) has been reported to promote high-grade glioma and is inhibited by metformin in other tumors, we explored whether metformin directly interferes with TGF-β2-signaling. Functional investigation of proliferation and migr ...[more]

PMID: 27163626

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Project description:High-grade gliomas, glioblastomas (GB), are refractory to conventional treatment combining surgery, chemotherapy, mainly temozolomide, and radiotherapy. This highlights an urgent need to develop novel therapies and increase the efficacy of radio/chemotherapy for these very aggressive and malignant brain tumors. Recently, tumor metabolism became an interesting potential therapeutic target in various cancers. Accordingly, combining drugs targeting cell metabolism with appropriate chemotherapeutic agents or radiotherapy has become attractive. In light of these perspectives, we were particularly interested in the anti-cancer properties of a biguanide molecule used for type 2 diabetes treatment, metformin. In our present work, we demonstrate that metformin decreases mitochondrial-dependent ATP production and oxygen consumption and increases lactate and glycolytic ATP production. We show that metformin induces decreased proliferation, cell cycle arrest, autophagy, apoptosis and cell death in vitro with a concomitant activation of AMPK, Redd1 and inhibition of the mTOR pathway. Cell sensitivity to metformin also depends on the genetic and mutational backgrounds of the different GB cells used in this study, particularly their PTEN status. Interestingly, knockdown of AMPK and Redd1 with siRNA partially, but incompletely, abrogates the induction of apoptosis by metformin suggesting both AMPK/Redd1-dependent and -independent effects. However, the primary determinant of the effect of metformin on cell growth is the genetic and mutational backgrounds of the glioma cells. We further demonstrate that metformin treatment in combination with temozolomide and/or irradiation induces a synergistic anti-tumoral response in glioma cell lines. Xenografts performed in nude mice demonstrate in vivo that metformin delays tumor growth. As current treatments for GB commonly fail to cure, the need for more effective therapeutic options is overwhelming. Based on these results, metformin could represent a potential enhancer of the cytotoxic effects of temozolomide and/or radiotherapy.

Dataset Information

Metformin inhibits proliferation and migration of glioblastoma cells independently of TGF-?2.

Publications

Metformin inhibits proliferation and migration of glioblastoma cells independently of TGF-β2.

Similar Datasets

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