The Inhibition of microRNA-128 on IGF-1-Activating mTOR Signaling Involves in Temozolomide-Induced Glioma Cell Apoptotic Death

Abstract

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.

Down‐Regulation of AQP4 Expression via p38 MAPK Signaling in Temozolomide‐Induced Glioma Cells Growth Inhibition and Invasion Impairment

“…The mechanisms for anti‐cancer effect of TMZ were very complicated, and had not yet been clear. The mechanisms may include breaking the glioma cells’ DNA [Fukai et al, ] or inhibiting Wnt3a/glycogen synthase‐3 kinase ß‐catenin, TROY, PI3K signaling pathway [Chen et al, ; Wu et al, ]. In present study, our data showed that TMZ had cytotoxic effect on glioma cells, which could significantly inhibit proliferation, affect differentiation of glioma cell by arresting the cell cycle in the G2/M phase.…”

Hypoxia- and acidosis-driven aberrations of secreted microRNAs in endometrial cancer in vitro

“…Furthermore, it has been associated with inhibition of the mTOR signaling pathway in glioblastomas. Decreased miR-128-1 expression levels in glioblastomas could be strongly associated with poor survival (87). The observed reduced expression levels of miR-128-1 in Ishikawa cells under hypoxic conditions may also account for a regulative function of miR-128-1 in EC.…”

Inhibition of Mir-128-3p by Tongxinluo Protects Human Cardiomyocytes From Ischemia/Reperfusion Injury via Upregulation of P70s6k1/P-P70s6k1

“…MiR-128-3p was implicated as important in multiple physiological and pathophysiological processes, such as angiogenesis, neuronal plasticity, cholesterol metabolism and differentiation Adlakha and Saini, 2014). Moreover, miR-128-3p inhibition in cells enhanced their resistance to detrimental stimuli like chemotherapeutic agents and H/R (Zhu et al, 2011;Chen et al, 2016;Zeng et al, 2016). The protective effects of TXL on HCMs during H/R were largely abolished by transfection with miR-128-3p, indicating that miR-128-3p mediated the beneficial effects of TXL on HCMs during H/R.…”