Naringin inhibits the invasion and migration of human glioblastoma cell via downregulation of MMP-2 and MMP-9 expression and inactivation of p38 signaling pathway.

International audienceGliomas are the most common and malignant primary brain tumors. They are associated with a poor prognosis despite the availability of multiple therapeutic options. Naringin, a common dietary flavonoid abundantly present in fruits and vegetables, is believed to possess strong anti-proliferative and anti-cancer properties. However, there are no reports describing its effects on the invasion and migration of glioblastoma cell lines. Our results showed that the treatment of U251 glioma cell lines with different concentrations of naringin inhibited the invasion and migration of these cells. In addition, we revealed a decrease in the levels of matrix metalloproteinases (MMP-2) and (MMP-9) expression as well as proteinase activity in U251 glioma cells. In contrast, the expression of tissue inhibitor of metalloproteinases (TIMP-1) and (TIMP-2) was increased. Furthermore, naringin treatment decreased significantly the phosphorylated level of p38. Combined treatment with a p38 inhibitor (SB203580) resulted in the synergistic reduction of MMP-2 and MMP-9 expressions correlated with an increase of TIMP-1 and TIMP-2 expressions and the anti-invasive properties. However, p38 chemical activator (anisomycin) could block these effects produced by naringin, suggesting a direct downregulation of the p38 signaling pathway. These data suggest that naringin may have therapeutic potential for controlling invasiveness of malignant gliomas by inhibiting of p38 signal transduction pathways

PTEN-regulated AKT/FoxO3a/Bim signaling contributes to Human cell glioblastoma apoptosis by platinum-maurocalcin conjugate

International audienceA previous report has shown that a chimera between a platinum complexing agent (1) andthe cell penetrating peptide maurocalcin, synthesized with D-amino acids, (DMCa), termedPt-1-DMCa, is a highly successful anticancer compound that works by targeting theintracellular redox system in glioblastoma (GBM) cells. However, the detailed cellularmechanism whereby the conjugate specifically kills tumor cells remains unclear. Herein, weshow that Pt-1-DMCa induces apoptosis in Human U87 GBM cells through reactive oxygenspecies (ROS)-dependent modulation of the PI3K/AKT/FoxO3a signalling pathway. First, wefound that Pt-1-DMCa treatment of these cells induces inhibition of AKT and nuclearaccumulation of FoxO3a thereby facilitating transcription of the target genes Bim and PTEN.Modulation of the AKT/FoxO3a/Bim signaling pathway by RNA interference confirms thatthese signaling events are critical for Pt-1-DMCa-induced apoptosis of U87 GBM cells.Furthermore, we reveal that FoxO3a-mediated up-regulation of PTEN exerts an additionalinhibitory effect on the AKT survival pathway. Thus, our results demonstrate that theconjugate can induce ROS-dependent FoxO3a-mediated apoptosis in U87 cells throughPTEN-mediated inhibition of the PI3K/AKT survival axis. Our results help elucidate themolecular mechanisms underlying Pt-1-DMCa-induced cell death in U87 GBM cells andsupport a theoretical basis for future applications of the MCa peptid