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