PMID- 27893811 OWN - NLM STAT- MEDLINE DCOM- 20170801 LR - 20211204 IS - 1932-6203 (Electronic) IS - 1932-6203 (Linking) VI - 11 IP - 11 DP - 2016 TI - The Inhibition of microRNA-128 on IGF-1-Activating mTOR Signaling Involves in Temozolomide-Induced Glioma Cell Apoptotic Death. PG - e0167096 LID - 10.1371/journal.pone.0167096 [doi] LID - e0167096 AB - Temozolomide (TMZ), an alkylating agent of the imidazotetrazine series, is a first-line chemotherapeutic drug used in the clinical therapy of glioblastoma multiforme, the most common and high-grade primary glioma in adults. Micro (mi)RNAs, which are small noncoding RNAs, post-transcriptionally regulate gene expressions and are involved in gliomagenesis. However, no studies have reported relationships between TMZ and miRNA gene regulation. We investigated TMZ-mediated miRNA profiles and its molecular mechanisms underlying the induction of glioma cell death. By performing miRNA microarray and bioinformatics analyses, we observed that expression of 248 miRNAs was altered, including five significantly upregulated and 17 significantly downregulated miRNAs, in TMZ-treated U87MG cells. miR-128 expression levels were lower in different glioma cells and strongly associated with poor survival. TMZ treatment significantly upregulated miR-128 expression. TMZ significantly enhanced miR-128-1 promoter activity and transcriptionally regulated miR-128 levels through c-Jun N-terminal kinase 2/c-Jun pathways. The overexpression and knockdown of miR-128 expression significantly affected TMZ-mediated cell viability and apoptosis-related protein expression. Furthermore, the overexpression of miR-128 alone enhanced apoptotic death of glioma cells through caspase-3/9 activation, poly(ADP ribose) polymerase degradation, reactive oxygen species generation, mitochondrial membrane potential loss, and non-protective autophagy formation. Finally, we identified that key members in mammalian target of rapamycin (mTOR) signaling including mTOR, rapamycin-insensitive companion of mTOR, insulin-like growth factor 1, and PIK3R1, but not PDK1, were direct target genes of miR-128. TMZ inhibited mTOR signaling through miR-128 regulation. These results indicate that miR-128-inhibited mTOR signaling is involved in TMZ-mediated cytotoxicity. Our findings may provide a better understanding of cytotoxic mechanisms of TMZ involved in glioblastoma development. FAU - Chen, Peng-Hsu AU - Chen PH AD - Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan. FAU - Cheng, Chia-Hsiung AU - Cheng CH AD - Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan. AD - Department of Biochemistry and Molecular Cell Biology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan. FAU - Shih, Chwen-Ming AU - Shih CM AD - Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan. AD - Department of Biochemistry and Molecular Cell Biology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan. FAU - Ho, Kuo-Hao AU - Ho KH AD - Department of Clinical Pharmacy, School of Pharmacy, Taipei Medical University, Taipei, Taiwan. FAU - Lin, Cheng-Wei AU - Lin CW AD - Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan. AD - Department of Biochemistry and Molecular Cell Biology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan. FAU - Lee, Chin-Cheng AU - Lee CC AD - Department of Pathology and Laboratory Medicine, Shin Kong Wu Ho-Su Memorial Hospital, Taipei, Taiwan. FAU - Liu, Ann-Jeng AU - Liu AJ AD - Department of Neurosurgery, Taipei City Hospital Ren-Ai Branch, Taipei, Taiwan. FAU - Chang, Cheng-Kuei AU - Chang CK AD - Department of Neurosurgery, Shuang Ho Hospital, Taipei Medical University, New Taipei City, Taiwan. AD - Graduate Institute of Injury Prevention and Control, Taipei Medical University, Taipei, Taiwan. FAU - Chen, Ku-Chung AU - Chen KC AUID- ORCID: 0000-0002-4696-3924 AD - Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan. AD - Department of Biochemistry and Molecular Cell Biology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan. LA - eng PT - Journal Article DEP - 20161128 PL - United States TA - PLoS One JT - PloS one JID - 101285081 RN - 0 (Antineoplastic Agents, Alkylating) RN - 0 (MIRN128 microRNA, human) RN - 0 (MicroRNAs) RN - 0 (Reactive Oxygen Species) RN - 67763-96-6 (Insulin-Like Growth Factor I) RN - 7GR28W0FJI (Dacarbazine) RN - EC 2.7.1.1 (MTOR protein, human) RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) RN - YF1K15M17Y (Temozolomide) SB - IM MH - Antineoplastic Agents, Alkylating/pharmacology MH - Apoptosis/*drug effects MH - Brain Neoplasms/drug therapy/genetics/*pathology MH - Dacarbazine/*analogs & derivatives/pharmacology MH - Glioma/drug therapy/genetics/*pathology MH - Humans MH - Insulin-Like Growth Factor I/genetics/*metabolism MH - Membrane Potential, Mitochondrial/drug effects MH - MicroRNAs/*genetics MH - Reactive Oxygen Species/metabolism MH - Signal Transduction/drug effects MH - Survival Rate MH - TOR Serine-Threonine Kinases/genetics/*metabolism MH - Temozolomide MH - Tumor Cells, Cultured PMC - PMC5125683 COIS- The authors have declared that no competing interests exist. EDAT- 2016/11/29 06:00 MHDA- 2017/08/02 06:00 PMCR- 2016/11/28 CRDT- 2016/11/29 06:00 PHST- 2016/07/13 00:00 [received] PHST- 2016/11/07 00:00 [accepted] PHST- 2016/11/29 06:00 [entrez] PHST- 2016/11/29 06:00 [pubmed] PHST- 2017/08/02 06:00 [medline] PHST- 2016/11/28 00:00 [pmc-release] AID - PONE-D-16-27955 [pii] AID - 10.1371/journal.pone.0167096 [doi] PST - epublish SO - PLoS One. 2016 Nov 28;11(11):e0167096. doi: 10.1371/journal.pone.0167096. eCollection 2016.