title: Metformin treatment reduces temozolomide resistance of glioblastoma cells.
abstract: It has been reported that metformin acts synergistically with temozolomide (TMZ) to inhibit proliferation of glioma cells including glioblastoma multiforme (GBM). However, the molecular mechanism underlying how metformin exerts its anti-cancer effects remains elusive. We used a combined experimental and bioinformatics approach to identify genes and complex regulatory/signal transduction networks that are involved in restoring TMZ sensitivity of GBM cells after metformin treatment. First, we established TMZ resistant GBM cell lines and found that the resistant cells regained TMZ sensitivity after metformin treatment. We further identified that metformin down-regulates SOX2 expression in TMZ-resistant glioma cells, reduces neurosphere formation capacity of glioblastoma cells, and inhibits GBM xenograft growth in vivo. Finally, the global gene expression profiling data reveals that multiple pathways are involved in metformin treatment related gene expression changes, including fatty acid metabolism and RNA binding and splicing pathways. Our work provided insight of the mechanisms on potential synergistic effects of TMZ and metformin in the treatment of glioblastoma, which will in turn yield potentially translational value for clinical applications.
authors: Department of Neurosurgery, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, Texas, USA.|Department of Neurosurgery, St. Vincent's Hospital, College of Medicine, The Catholic University of Korea, Suwon, South Korea.|Center for Stem Cell and Regenerative Medicine, The Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, Texas, USA.
authors: Seung Ho
authors: SH
authors: Yang
authors: Department of Neurosurgery, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, Texas, USA.|Center for Stem Cell and Regenerative Medicine, The Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, Texas, USA.
authors: Shenglan
authors: S
authors: Li
authors: Department of Neurosurgery, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, Texas, USA.
authors: Guangrong
authors: G
authors: Lu
authors: Department of Neurosurgery, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, Texas, USA.|Center for Stem Cell and Regenerative Medicine, The Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, Texas, USA.
authors: Haipeng
authors: H
authors: Xue
authors: Department of Neurosurgery, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, Texas, USA.|Center for Stem Cell and Regenerative Medicine, The Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, Texas, USA.
authors: Dong H
authors: DH
authors: Kim
authors: Department of Neurosurgery, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, Texas, USA.
authors: Jay-Jiguang
authors: JJ
authors: Zhu
authors: Department of Neurosurgery, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, Texas, USA.|Center for Stem Cell and Regenerative Medicine, The Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, Texas, USA.
authors: Ying
authors: Y
authors: Liu
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects*; D003606:Dacarbazine / Q000031:analogs & derivatives* / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm; D015972:Gene Expression Regulation, Neoplastic; D053263:Gene Regulatory Networks; D005909:Glioblastoma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D006801:Humans; D020128:Inhibitory Concentration 50; D008687:Metformin / Q000494:pharmacology*; D016513:Mice, SCID; D009361:Neoplasm Invasiveness; D055748:SOXB1 Transcription Factors / Q000235:genetics / Q000378:metabolism; D000077204:Temozolomide; D013997:Time Factors; D059467:Transcriptome; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: C527782:SOX2 protein, human; D055748:SOXB1 Transcription Factors; D003606:Dacarbazine; D008687:Metformin; D000077204:Temozolomide
keywords: SOX2; glioblastoma; global gene expression; metformin; temozolomide resistance