MicroRNA-21 Knockdown Disrupts Glioma Growth In vivo and Displays Synergistic Cytotoxicity with Neural Precursor Cell–Delivered S-TRAIL in Human Gliomas

Abstract

Despite the development of new glioma therapies that allow for tumor-targeted in situ delivery of cytotoxic drugs, tumor resistance to apoptosis remains a key impediment to effective treatment. Mounting evidence indicates that microRNAs (miRNA) might play a fundamental role in tumorigenesis, controlling cell proliferation and apoptosis. In gliomas, microRNA-21 (miR-21) levels have been reported to be elevated and their knockdown is associated with increased apoptotic activity. We hypothesized that suppression of miR-21 might sensitize gliomas for cytotoxic tumor therapy. With the use of locked nucleic acid (LNA)-antimiR-21 oligonucleotides, bimodal imaging vectors, and neural precursor cells (NPC) expressing a secretable variant of the cytotoxic agent tumor necrosis factor-related apoptosis inducing ligand (S-TRAIL), we show that the combined suppression of miR-21 and NPC-S-TRAIL leads to a synergistic increase in caspase activity and significantly decreased cell viability in human glioma cells in vitro. This phenomenon persists in vivo, as we observed complete eradication of LNA-antimiR-21-treated gliomas subjected to the presence of NPC-S-TRAIL in the murine brain. Our results reveal the efficacy of miR-21 antagonism in murine glioma models and implicate miR-21 as a target for therapeutic intervention. Furthermore, our findings provide the basis for developing combination therapies using miRNA modulation and cytotoxic tumor therapies.

MicroRNA signatures of TRAIL resistance in human non-small cell lung cancer

“…Mott et al (2007) described that miR-29b is able to regulate Mcl1-1 protein and thus TRAIL-mediated cytotoxicity in cholangiocarcinoma cell lines. Corsten et al (2007) demonstrated that the combined effect of miR-21 antagonism and soluble TRAIL delivery in glioma cells leads to increase in caspase activity and cell death in glioma cells. More recently, Ovcharenko et al (2007) described a genome-scale miRs and RNAi screen in breast cancer cells.…”

MiR‐483–5p suppresses the proliferation of glioma cells via directly targeting ERK1

“…However, only a small fraction of miRNAs have been experimentally examined, among which miR-21 has been well-studied in gliomas. miR-21, which is up-regulated in many solid tumors, inhibits caspase-3 dependent apoptosis in glioma cells and promotes tumor formation in vivo [4]. MiR-21 also facilitates cell invasion by directly targeting metalloprotease inhibitors TIMP3 and RECK [5].…”

An autoregulatory loop mediated by miR-21 and PDCD4 controls the AP-1 activity in RAS transformation

“…In addition, miR-21 expression is induced by cytotoxic drugs, such as gemcitabine in cholangiocarcinoma cells, in which the experimental inhibition of miR-21 is able to increase the sensitivity to chemotherapeutic agents (Meng et al, 2006). Remarkably, in a murine model of glioma growth, tumor cell treatment with the anti-miR-21 LNA, exhibiting synergistic cytotoxicity in combination with S-TRAIL, allowed to obtain complete eradication of cancer growth in vivo (Corsten et al, 2007).…”