PTEN-regulated AKT/FoxO3a/Bim signaling contributes to Human cell glioblastoma apoptosis by platinum-maurocalcin conjugate
Résumé
A previous report has shown that a chimera between a platinum complexing agent (1) and
the cell penetrating peptide maurocalcin, synthesized with D-amino acids, (DMCa), termed
Pt-1-DMCa, is a highly successful anticancer compound that works by targeting the
intracellular redox system in glioblastoma (GBM) cells. However, the detailed cellular
mechanism whereby the conjugate specifically kills tumor cells remains unclear. Herein, we
show that Pt-1-DMCa induces apoptosis in Human U87 GBM cells through reactive oxygen
species (ROS)-dependent modulation of the PI3K/AKT/FoxO3a signalling pathway. First, we
found that Pt-1-DMCa treatment of these cells induces inhibition of AKT and nuclear
accumulation of FoxO3a thereby facilitating transcription of the target genes Bim and PTEN.
Modulation of the AKT/FoxO3a/Bim signaling pathway by RNA interference confirms that
these 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 additional
inhibitory effect on the AKT survival pathway. Thus, our results demonstrate that the
conjugate can induce ROS-dependent FoxO3a-mediated apoptosis in U87 cells through
PTEN-mediated inhibition of the PI3K/AKT survival axis. Our results help elucidate the
molecular mechanisms underlying Pt-1-DMCa-induced cell death in U87 GBM cells and
support a theoretical basis for future applications of the MCa peptide
Domaines
Sciences du Vivant [q-bio]Origine | Fichiers produits par l'(les) auteur(s) |
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