title: Metformin inhibits proliferation and migration of glioblastoma cells independently of TGF-β2.
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 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 migration of primary BTICs after treatment with metformin+/-TGF-β2 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-β2 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-β2 mRNA expression (qRT-PCR), TGF-β2 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-β2-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.
authors.affiliation: a Department of Neurology and Wilhelm Sander-NeuroOncology Unit , University Hospital Regensburg , Regensburg , Germany.
authors.forename: Corinna
authors.initials: C
authors.lastname: Seliger
authors.affiliation: a Department of Neurology and Wilhelm Sander-NeuroOncology Unit , University Hospital Regensburg , Regensburg , Germany.
authors.forename: Anne-Louise
authors.initials: AL
authors.lastname: Meyer
authors.affiliation: b Department of Internal Medicine III , University Hospital Regensburg , Regensburg , Germany.
authors.forename: Kathrin
authors.initials: K
authors.lastname: Renner
authors.affiliation: a Department of Neurology and Wilhelm Sander-NeuroOncology Unit , University Hospital Regensburg , Regensburg , Germany.
authors.forename: Verena
authors.initials: V
authors.lastname: Leidgens
authors.affiliation: a Department of Neurology and Wilhelm Sander-NeuroOncology Unit , University Hospital Regensburg , Regensburg , Germany.
authors.forename: Sylvia
authors.initials: S
authors.lastname: Moeckel
authors.affiliation: a Department of Neurology and Wilhelm Sander-NeuroOncology Unit , University Hospital Regensburg , Regensburg , Germany.
authors.forename: Birgit
authors.initials: B
authors.lastname: Jachnik
authors.affiliation: c Institute of Functional Genomics, University of Regensburg , Regensburg , Germany.
authors.forename: Katja
authors.initials: K
authors.lastname: Dettmer
authors.affiliation: a Department of Neurology and Wilhelm Sander-NeuroOncology Unit , University Hospital Regensburg , Regensburg , Germany.
authors.forename: Ulrike
authors.initials: U
authors.lastname: Tischler
authors.affiliation: a Department of Neurology and Wilhelm Sander-NeuroOncology Unit , University Hospital Regensburg , Regensburg , Germany.
authors.forename: Valeria
authors.initials: V
authors.lastname: Gerthofer
authors.affiliation: a Department of Neurology and Wilhelm Sander-NeuroOncology Unit , University Hospital Regensburg , Regensburg , Germany.
authors.forename: Lisa
authors.initials: L
authors.lastname: Rauer
authors.affiliation: d Department of Neurology , University Hospital Erlangen , Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Uhl
authors.affiliation: e Department of Neurosurgery , University Hospital Regensburg , Regensburg , Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Proescholdt
authors.affiliation: a Department of Neurology and Wilhelm Sander-NeuroOncology Unit , University Hospital Regensburg , Regensburg , Germany.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Bogdahn
authors.affiliation: f Department of Neuropathology , Regensburg University Hospital , Regensburg , Germany.
authors.forename: Markus J
authors.initials: MJ
authors.lastname: Riemenschneider
authors.affiliation: c Institute of Functional Genomics, University of Regensburg , Regensburg , Germany.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Oefner
authors.affiliation: b Department of Internal Medicine III , University Hospital Regensburg , Regensburg , Germany.
authors.forename: Marina
authors.initials: M
authors.lastname: Kreutz
authors.affiliation: a Department of Neurology and Wilhelm Sander-NeuroOncology Unit , University Hospital Regensburg , Regensburg , Germany.
authors.forename: Arabel
authors.initials: A
authors.lastname: Vollmann-Zwerenz
authors.affiliation: a Department of Neurology and Wilhelm Sander-NeuroOncology Unit , University Hospital Regensburg , Regensburg , Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Hau
mesh_terms: D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D005909:Glioblastoma / Q000473:pathology*; D006801:Humans; D008687:Metformin / Q000494:pharmacology*; D008954:Models, Biological; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D053781:Transforming Growth Factor beta2 / Q000235:genetics / Q000378:metabolism*
chemical_list: D012333:RNA, Messenger; D053781:Transforming Growth Factor beta2; D008687:Metformin
keywords: AMPK; BTIC; SMAD; TGF-β2; glioblastoma; mTOR; metformin