Metformin treatment reduces temozolomide resistance of glioblastoma cells

// Seung Ho Yang 1, 2, 3, * , Shenglan Li 1, 3, * , Guangrong Lu 1 , Haipeng Xue 1, 3 , Dong H. Kim 1, 3 , Jay-Jiguang Zhu 1, ** , Ying Liu 1, 3, ** 1 Department of Neurosurgery, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, Texas, USA 2 Department of Neurosurgery, St. Vincent’s Hospital, College of Medicine, The Catholic University of Korea, Suwon, South Korea 3 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 * These authors contributed equally to this work ** These authors contributed equally to this work Correspondence to: Jay-Jiguang Zhu, email: jay.jiguang.zhu@uth.tmc.edu Ying Liu, email: ying.liu@uth.tmc.edu Keywords: glioblastoma, metformin, temozolomide resistance, SOX2, global gene expression Received: September 07, 2016 Accepted: October 14, 2016 Published: October 24, 2016 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.