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

References

• Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ, Belanger K, Brandes AA, Marosi C, Bogdahn U, et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 2005; 352:987-96; PMID:15758009; http://dx.doi.org/10.1056/NEJMoa043330
   PubMed Web of Science ®Google Scholar
• Stupp R, Hegi ME, Gorlia T, Erridge SC, Perry J, Hong YK, Aldape KD, Lhermitte B, Pietsch T, Grujicic D, et al. Cilengitide combined with standard treatment for patients with newly diagnosed glioblastoma with methylated MGMT promoter (CENTRIC EORTC 26071–22072 study): a multicentre, randomised, open-label, phase 3 trial. Lancet Oncol 2014; 15:1100-8; PMID:25163906; http://dx.doi.org/10.1016/S1470-2045(14)70379-1
   PubMed Web of Science ®Google Scholar
• Paw I, Carpenter RC, Watabe K, Debinski W, Lo HW. Mechanisms regulating glioma invasion. Cancer Lett 2015; 362:1-7; PMID:25796440; http://dx.doi.org/10.1016/j.canlet.2015.03.015
   PubMed Web of Science ®Google Scholar
• Jhaveri N, Chen TC, Hofman FM. Tumor vasculature and glioma stem cells: Contributions to glioma progression. Cancer Lett 2014: http://dx.doi.org/10.1016/j.canlet.2014.12.028; PMID:25527451
   Google Scholar
• Avril T, Vauleon E, Tanguy-Royer S, Mosser J, Quillien V. Mechanisms of immunomodulation in human glioblastoma. Immunotherapy 2011; 3(4 Suppl):42-4; PMID:21524170; http://dx.doi.org/10.2217/imt.11.39
   PubMed Web of Science ®Google Scholar
• Lathia JD, Mack SC, Mulkearns-Hubert EE, Valentim CL, Rich JN. Cancer stem cells in glioblastoma. Genes Dev 2015; 29:1203-17; PMID:26109046; http://dx.doi.org/10.1101/gad.261982.115
   PubMed Web of Science ®Google Scholar
• Wick W, Naumann U, Weller M. Transforming growth factor-β: a molecular target for the future therapy of glioblastoma. Curr Pharm Des 2006; 12:341-9; PMID:16454748; http://dx.doi.org/10.2174/138161206775201901
   PubMed Web of Science ®Google Scholar
• Riemenschneider MJ, Hirblinger M, Vollmann-Zwerenz A, Hau P, Proescholdt MA, Jaschinski F, Rothhammer-Hampl T, Wosikowski K, Janicot M, Leo E. TGF-ss isoforms in cancer: Immunohistochemical expression and Smad-pathway-activity-analysis in thirteen major tumor types with a critical appraisal of antibody specificity and immunohistochemistry assay validity. Oncotarget 2015; 6:26770-81; PMID:26450853; http://dx.doi.org/10.18632/oncotarget.5780
   PubMed Web of Science ®Google Scholar
• Hau P, Jachimczak P, Schlaier J, Bogdahn U. TGF-beta2 signaling in high-grade gliomas. Curr Pharm Biotechnol 2011; 12:2150-7; PMID:21619538; http://dx.doi.org/10.2174/138920111798808347
   PubMed Web of Science ®Google Scholar
• Beier CP, Kumar P, Meyer K, Leukel P, Bruttel V, Aschenbrenner I, Riemenschneider MJ, Fragoulis A, Rummele P, Lamszus K, et al. The cancer stem cell subtype determines immune infiltration of glioblastoma. Stem Cells Dev 2012; 21:2753-61; PMID:22676416; http://dx.doi.org/10.1089/scd.2011.0660
   PubMed Web of Science ®Google Scholar
• Kuczynski EA, Patten SG, Coomber BL. VEGFR2 expression and TGF-β signaling in initial and recurrent high-grade human glioma. Oncology 2011; 81:126-34; PMID:21985798; http://dx.doi.org/10.1159/000332849
   PubMed Web of Science ®Google Scholar
• Weller M, Fontana A. The failure of current immunotherapy for malignant glioma. Tumor-derived TGF-β, T-cell apoptosis, and the immune privilege of the brain. Brain Res 1995; 21:128-51; PMID:8866671; http://dx.doi.org/10.1016/0165-0173(95)00010-0
   PubMed Web of Science ®Google Scholar
• Frei K, Gramatzki D, Tritschler I, Schroeder JJ, Espinoza L, Rushing EJ, Weller M. Transforming growth factor-β pathway activity in glioblastoma. Oncotarget 2015; 6:5963-77; PMID:25849941; http://dx.doi.org/10.18632/oncotarget.3467
   PubMed Web of Science ®Google Scholar
• Ferrannini E. The target of metformin in type 2 diabetes. N Engl J Med 2014; 371:1547-8; PMID:25317875; http://dx.doi.org/10.1056/NEJMcibr1409796
   PubMed Web of Science ®Google Scholar
• Yin M, Zhou J, Gorak EJ, Quddus F. Metformin is associated with survival benefit in cancer patients with concurrent type 2 diabetes: a systematic review and meta-analysis. Oncologist 2013; 18:1248-55; PMID:24258613; http://dx.doi.org/10.1634/theoncologist.2013-0111
   PubMed Web of Science ®Google Scholar
• Isakovic A, Harhaji L, Stevanovic D, Markovic Z, Sumarac-Dumanovic M, Starcevic V, Micic D, Trajkovic V. Dual antiglioma action of metformin: cell cycle arrest and mitochondria-dependent apoptosis. Cell Mol Life Sci 2007; 64:1290-302; PMID:17447005; http://dx.doi.org/10.1007/s00018-007-7080-4
   PubMed Web of Science ®Google Scholar
• Wurth R, Pattarozzi A, Gatti M, Bajetto A, Corsaro A, Parodi A, Sirito R, Massollo M, Marini C, Zona G, Fenoglio D, Sambuceti G, Filaci G, Daga A, Barbieri F, Florio T. Metformin selectively affects human glioblastoma tumor-initiating cell viability: A role for metformin-induced inhibition of Akt. Cell Cycle 2012; 12:145-56; PMID:23255107; http://dx.doi.org/10.4161/cc.23050
   PubMed Web of Science ®Google Scholar
• Gritti M, Wurth R, Angelini M, Barbieri F, Peretti M, Pizzi E, Pattarozzi A, Carra E, Sirito R, Daga A, Curmi PM, Mazzanti M, Florio T. Metformin repositioning as antitumoral agent: selective antiproliferative effects in human glioblastoma stem cells, via inhibition of CLIC1-mediated ion current. Oncotarget 2014; 5:11252-68; PMID:25361004; http://dx.doi.org/10.18632/oncotarget.2617
   PubMed Web of Science ®Google Scholar
• Yu Z, Zhao G, Xie G, Zhao L, Chen Y, Yu H, Zhang Z, Li C, Li Y. Metformin and temozolomide act synergistically to inhibit growth of glioma cells and glioma stem cells in vitro and in vivo. Oncotarget 2015; 6:32930-43; PMID:26431379
   PubMed Web of Science ®Google Scholar
• Sesen J, Dahan P, Scotland SJ, Saland E, Dang VT, Lemarie A, Tyler BM, Brem H, Toulas C, Cohen-Jonathan Moyal E, Sarry JE, Skuli N. Metformin inhibits growth of human glioblastoma cells and enhances therapeutic response. PloS One 2015; 10:e0123721; PMID:25867026; http://dx.doi.org/10.1371/journal.pone.0123721
   PubMed Web of Science ®Google Scholar
• Gao LB, Tian S, Gao HH, Xu YY. Metformin inhibits glioma cell U251 invasion by downregulation of fibulin-3. Neuroreport 2013; 24:504-8; PMID:23660683; http://dx.doi.org/10.1097/WNR.0b013e32836277fb
   PubMed Web of Science ®Google Scholar
• Sato A, Sunayama J, Okada M, Watanabe E, Seino S, Shibuya K, Suzuki K, Narita Y, Shibui S, Kayama T, Kitanaka C. Glioma-initiating cell elimination by metformin activation of FOXO3 via AMPK. Stem Cells Transl Med 2013; 1:811-24; http://dx.doi.org/10.5966/sctm.2012-0058
   Web of Science ®Google Scholar
• Mouhieddine TH, Nokkari A, Itani MM, Chamaa F, Bahmad H, Monzer A, El-Merahbi R, Daoud G, Eid A, Kobeissy FH, Abou-Kheir W. Metformin and Ara-a Effectively Suppress Brain Cancer by Targeting Cancer Stem/Progenitor Cells. Front Neurosci 2015; 9:442; PMID:26635517; http://dx.doi.org/10.3389/fnins.2015.00442
   PubMed Web of Science ®Google Scholar
• Yu Z, Zhao G, Li P, Li Y, Zhou G, Chen Y, Xie G. Temozolomide in combination with metformin act synergistically to inhibit proliferation and expansion of glioma stem-like cells. Oncology Lett 2016; 11:2792-800; PMID:27073554
   PubMed Web of Science ®Google Scholar
• Wurth R, Pattarozzi A, Gatti M, Bajetto A, Corsaro A, Parodi A, Sirito R, Massollo M, Marini C, Zona G, et al. Metformin selectively affects human glioblastoma tumor-initiating cell viability: A role for metformin-induced inhibition of Akt. Cell Cycle 2013; 12:145-56; PMID:23255107; http://dx.doi.org/10.4161/cc.23050
   PubMed Web of Science ®Google Scholar
• Owen MR, Doran E, Halestrap AP. Evidence that metformin exerts its anti-diabetic effects through inhibition of complex 1 of the mitochondrial respiratory chain. Biochem J 2000; 348 Pt 3:607-14; PMID:10839993; http://dx.doi.org/10.1042/bj3480607
   PubMed Web of Science ®Google Scholar
• Vazquez-Martin A, Oliveras-Ferraros C, Cufi S, Del Barco S, Martin-Castillo B, Menendez JA. Metformin regulates breast cancer stem cell ontogeny by transcriptional regulation of the epithelial-mesenchymal transition (EMT) status. Cell Cycle 2010; 9:3807-14; PMID:20890129; http://dx.doi.org/10.4161/cc.9.18.13131
   PubMed Web of Science ®Google Scholar
• Cufi S, Vazquez-Martin A, Oliveras-Ferraros C, Martin-Castillo B, Joven J, Menendez JA. Metformin against TGFbeta-induced epithelial-to-mesenchymal transition (EMT): from cancer stem cells to aging-associated fibrosis. Cell Cycle 2010; 9:4461-8; PMID:21088486; http://dx.doi.org/10.4161/cc.9.22.14048
   PubMed Web of Science ®Google Scholar
• Jung GS, Jeon JH, Choi YK, Jang SY, Park SY, Kim MK, Shin EC, Jeong WI, Lee IK, Kang YN, Park KG. Small heterodimer partner attenuates profibrogenic features of hepatitis C virus-infected cells. Liver Int 2015; 35:2233-45; PMID:25976932; http://dx.doi.org/10.1111/liv.12871
   PubMed Web of Science ®Google Scholar
• Dong Z, Chen CX. Effect of catalpol on diabetic nephropathy in rats. Phytomedicine 2013; 20:1023-9; PMID:23746755; http://dx.doi.org/10.1016/j.phymed.2013.04.007
   PubMed Web of Science ®Google Scholar
• Zhang X, Zhang C, Shen S, Xia Y, Yi L, Gao Q, Wang Y. Dehydroepiandrosterone induces ovarian and uterine hyperfibrosis in female rats. Hum Reprod 2013; 28:3074-85; PMID:23980058; http://dx.doi.org/10.1093/humrep/det341
   PubMed Web of Science ®Google Scholar
• Xavier DO, Amaral LS, Gomes MA, Rocha MA, Campos PR, Cota BD, Tafuri LS, Paiva AM, Silva JH, Andrade SP, et al. Metformin inhibits inflammatory angiogenesis in a murine sponge model. Biomed Pharmacother 2010; 64:220-5; PMID:20053525; http://dx.doi.org/10.1016/j.biopha.2009.08.004
   PubMed Web of Science ®Google Scholar
• Kim BH, Han S, Lee H, Park CH, Chung YM, Shin K, Lee HG, Ye SK. Metformin enhances the anti-adipogenic effects of atorvastatin via modulation of STAT3 and TGF-β/Smad3 signaling. Biochem Biophys Res Commun 2015; 456:173-8; PMID:25462562; http://dx.doi.org/10.1016/j.bbrc.2014.11.054
   PubMedGoogle Scholar
• Park IH, Um JY, Hong SM, Cho JS, Lee SH, Lee SH, Lee HM. Metformin reduces TGF-beta1-induced extracellular matrix production in nasal polyp-derived fibroblasts. Otolaryngol Head Neck Surg 2014; 150:148-53; PMID:24357397; http://dx.doi.org/10.1177/0194599813513880
   PubMed Web of Science ®Google Scholar
• Oliveras-Ferraros C, Cufi S, Vazquez-Martin A, Torres-Garcia VZ, Del Barco S, Martin-Castillo B, Menendez JA. Micro(mi)RNA expression profile of breast cancer epithelial cells treated with the anti-diabetic drug metformin: induction of the tumor suppressor miRNA let-7a and suppression of the TGFbeta-induced oncomiR miRNA-181a. Cell Cycle 2011; 10:1144-51; PMID:21368581; http://dx.doi.org/10.4161/cc.10.7.15210
   PubMed Web of Science ®Google Scholar
• Zhang J, Shen C, Wang L, Ma Q, Xia P, Qi M, Yang M, Han B. Metformin inhibits epithelial-mesenchymal transition in prostate cancer cells: involvement of the tumor suppressor miR30a and its target gene SOX4. Biochem Biophys Res Commun 2014; 452:746-52; PMID:25201727; http://dx.doi.org/10.1016/j.bbrc.2014.08.154
   PubMed Web of Science ®Google Scholar
• Thakur S, Viswanadhapalli S, Kopp JB, Shi Q, Barnes JL, Block K, Gorin Y, Abboud HE. Activation of AMP-activated protein kinase prevents TGF-beta1-induced epithelial-mesenchymal transition and myofibroblast activation. Am J Pathol 2015; 185:2168-80; PMID:26071397; http://dx.doi.org/10.1016/j.ajpath.2015.04.014
   PubMed Web of Science ®Google Scholar
• Lu J, Shi J, Li M, Gui B, Fu R, Yao G, Duan Z, Lv Z, Yang Y, Chen Z, Jia L, Tian L. Activation of AMPK by metformin inhibits TGF-β-induced collagen production in mouse renal fibroblasts. Life Sci 2015; 127:59-65; PMID:25744403; http://dx.doi.org/10.1016/j.lfs.2015.01.042
   PubMed Web of Science ®Google Scholar
• Maheshwari RA, Balaraman R, Sen AK, Seth AK. Effect of coenzyme Q10 alone and its combination with metformin on streptozotocin-nicotinamide-induced diabetic nephropathy in rats. Indian J Pharmacol 2014; 46:627-32; PMID:25538335; http://dx.doi.org/10.4103/0253-7613.144924
   PubMed Web of Science ®Google Scholar
• Gu J, Ye S, Wang S, Sun W, Hu Y. Metformin inhibits nuclear factor-kappaB activation and inflammatory cytokines expression induced by high glucose via adenosine monophosphate-activated protein kinase activation in rat glomerular mesangial cells in vitro. Chinese Med J 2014; 127:1755-60; PMID:24791887
   PubMed Web of Science ®Google Scholar
• Lee JH, Kim JH, Kim JS, Chang JW, Kim SB, Park JS, Lee SK. AMP-activated protein kinase inhibits TGF-β-, angiotensin II-, aldosterone-, high glucose-, and albumin-induced epithelial-mesenchymal transition. Am J Physiol Renal Physiol 2013; 304:F686-97; PMID:23324179
   PubMed Web of Science ®Google Scholar
• Cha HN, Choi JH, Kim YW, Kim JY, Ahn MW, Park SY. Metformin Inhibits Isoproterenol-induced Cardiac Hypertrophy in Mice. Korean J Physiol Pharmacol 2010; 14:377-84; PMID:21311678; http://dx.doi.org/10.4196/kjpp.2010.14.6.377
   PubMed Web of Science ®Google Scholar
• Wang XF, Zhang JY, Li L, Zhao XY. Beneficial effects of metformin on primary cardiomyocytes via activation of adenosine monophosphate-activated protein kinase. Chin Med J 2011; 124:1876-84; PMID:21740847
   PubMed Web of Science ®Google Scholar
• Seliger C, Leukel P, Moeckel S, Jachnik B, Lottaz C, Kreutz M, Brawanski A, Proescholdt M, Bogdahn U, Bosserhoff AK, Vollmann-Zwerenz A, Hau P. Lactate-modulated induction of THBS-1 activates transforming growth factor (TGF)-beta2 and migration of glioma cells in vitro. PloS one 2014 8:e78935; http://dx.doi.org/10.1371/journal.pone.0078935
   Google Scholar
• Annes JP, Munger JS, Rifkin DB. Making sense of latent TGFbeta activation. J Cell Sci 2003; 116:217-24; PMID:12482908; http://dx.doi.org/10.1242/jcs.00229
   PubMed Web of Science ®Google Scholar
• Brantley EC, Benveniste EN. Signal transducer and activator of transcription-3: a molecular hub for signaling pathways in gliomas. Mol Cancer Res 2008; 6:675-84; PMID:18505913; http://dx.doi.org/10.1158/1541-7786.MCR-07-2180
   PubMed Web of Science ®Google Scholar
• Carmignani M, Volpe AR, Aldea M, Soritau O, Irimie A, Florian IS, Tomuleasa C, Baritchii A, Petrushev B, Crisan G, Valle G. Glioblastoma stem cells: a new target for metformin and arsenic trioxide. J Biol Regul Homeostat Agents 2014; 28:1-15; PMID:24750786
   PubMed Web of Science ®Google Scholar
• Labuzek K, Suchy D, Gabryel B, Bielecka A, Liber S, Okopien B. Quantification of metformin by the HPLC method in brain regions, cerebrospinal fluid and plasma of rats treated with lipopolysaccharide. Pharmacol Rep 2010; 62:956-65; PMID:21098880; http://dx.doi.org/10.1016/S1734-1140(10)70357-1
   PubMed Web of Science ®Google Scholar
• Wilcock C, Bailey CJ. Accumulation of metformin by tissues of the normal and diabetic mouse. Xenobiotica 1994; 24:49-57; PMID:8165821; http://dx.doi.org/10.3109/00498259409043220
   PubMed Web of Science ®Google Scholar
• http://www.sz-produkte.de/pdf/fi/2014_10_51007278_fi_met_sz_500_850mg_it.pdf.
   Google Scholar
• Hannigan A, Smith P, Kalna G, Lo Nigro C, Orange C, O'Brien DI, Shah R, Syed N, Spender LC, Herrera B, et al. Epigenetic downregulation of human disabled homolog 2 switches TGF-β from a tumor suppressor to a tumor promoter. J Clin Invest 2010; 120:2842-57; PMID:20592473; http://dx.doi.org/10.1172/JCI36125
   PubMed Web of Science ®Google Scholar
• Lim JY, Oh MA, Kim WH, Sohn HY, Park SI. AMP-activated protein kinase inhibits TGF-β-induced fibrogenic responses of hepatic stellate cells by targeting transcriptional coactivator p300. J Cell Physiol 2012; 227:1081-9; PMID:21567395; http://dx.doi.org/10.1002/jcp.22824
   PubMed Web of Science ®Google Scholar
• Lin H, Li N, He H, Ying Y, Sunkara S, Luo L, Lv N, Huang D, Luo Z. AMPK Inhibits the Stimulatory Effects of TGF-β on Smad2/3 Activity, Cell Migration, and Epithelial-to-Mesenchymal Transition. Mol Pharmacol 2015; 88:1062-71; PMID:26424816; http://dx.doi.org/10.1124/mol.115.099549
   PubMed Web of Science ®Google Scholar
• Zhao Z, Cheng X, Wang Y, Han R, Li L, Xiang T, He L, Long H, Zhu B, He Y. Metformin inhibits the IL-6-induced epithelial-mesenchymal transition and lung adenocarcinoma growth and metastasis. PloS One 2014; 9:e95884; PMID:24789104; http://dx.doi.org/10.1371/journal.pone.0095884
   PubMedGoogle Scholar
• Moeckel S, Meyer K, Leukel P, Heudorfer F, Seliger C, Stangl C, Bogdahn U, Proescholdt M, Brawanski A, Vollmann-Zwerenz A, et al. Response-predictive gene expression profiling of glioma progenitor cells in vitro. PloS one 2014; 9:e108632; PMID:25268354; http://dx.doi.org/10.1371/journal.pone.0108632
   PubMedGoogle Scholar
• Esteller M, Hamilton SR, Burger PC, Baylin SB, Herman JG. Inactivation of the DNA repair gene O6-methylguanine-DNA methyltransferase by promoter hypermethylation is a common event in primary human neoplasia. Cancer Res 1999; 59:793-7; PMID:10029064
   PubMed Web of Science ®Google Scholar
• Pollard SM, Yoshikawa K, Clarke ID, Danovi D, Stricker S, Russell R, Bayani J, Head R, Lee M, Bernstein M, et al. Glioma stem cell lines expanded in adherent culture have tumor-specific phenotypes and are suitable for chemical and genetic screens. Cell Stem Cell 2009; 4:568-80; PMID:19497285; http://dx.doi.org/10.1016/j.stem.2009.03.014
   PubMed Web of Science ®Google Scholar
• Dettmer K, Aronov PA, Hammock BD. Mass spectrometry-based metabolomics. Mass Spectrom Rev 2007; 26:51-78; PMID:16921475; http://dx.doi.org/10.1002/mas.20108
   PubMed Web of Science ®Google Scholar
• Jain M, Nilsson R, Sharma S, Madhusudhan N, Kitami T, Souza AL, Kafri R, Kirschner MW, Clish CB, Mootha VK. Metabolite profiling identifies a key role for glycine in rapid cancer cell proliferation. Science 2012; 336:1040-4; PMID:22628656; http://dx.doi.org/10.1126/science.1218595
   PubMed Web of Science ®Google Scholar
• Schneider CA, Rasband WS, Eliceiri KW. NIH Image to ImageJ: 25 years of image analysis. Nat Methods 2012; 9:671-5; PMID:22930834; http://dx.doi.org/10.1038/nmeth.2089
   PubMed Web of Science ®Google Scholar
• Gogolla N, Galimberti I, DePaola V, Caroni P. Staining protocol for organotypic hippocampal slice cultures. Nat Protoc 2006; 1:2452-6; PMID:17406491; http://dx.doi.org/10.1038/nprot.2006.180
   PubMed Web of Science ®Google Scholar
• Gogolla N, Galimberti I, DePaola V, Caroni P. Preparation of organotypic hippocampal slice cultures for long-term live imaging. Nat Protoc 2006; 1:1165-71; PMID:17406399; http://dx.doi.org/10.1038/nprot.2006.168
   PubMed Web of Science ®Google Scholar
• Eyupoglu IY, Hahnen E, Heckel A, Siebzehnrubl FA, Buslei R, Fahlbusch R, Blumcke I. Malignant glioma-induced neuronal cell death in an organotypic glioma invasion model. Technical note. J Neurosurgery 2005; 102:738-44; PMID:15871520; http://dx.doi.org/10.3171/jns.2005.102.4.0738
   PubMed Web of Science ®Google Scholar