Numerous human cancers including radio-resistant human glioblastomas require a constitutive activation of the PI3K-Akt pathway for their survival. In this context the protein phosphatase-2A (PP2A) family of ser/thr protein phosphatases is a central regulator of cell homeostasis that counteracts the aberrant oncogenic PI3K survival signal. Importantly the trimeric ABαC holoenzyme, named PP2A1, specifically counteracts the aberrant oncogenic constitutively activated PI3K survival signal. In this regard we recently reported that the pharmacological activation of PP2A mediated by the sphingolipid analog FTY720 down-regulated the constitutively active PI3K/Akt pathway involved in the survival of radio-resistant U87G human glioblastoma cells. In this study, using a peptide-based drug phosphatase technology (DPT) we rational designed a new PP2A activator corresponding to an ApoE-mimetic bipartite-peptide, named DPT-Cog, that combines the cellular inactive DPT-sh1 shuttle (VKKKKIKREIKI) and the PP2A activating COG133 sequence (LRVRLASHLRK LRKRLL). We first demonstrated that this new chimeric DPT-sequence down-regulated the PI3K-Akt survival pathway and inhibited the survival of U87G cells. In addition we found that DPT-Cog decreased the growth of human glioblastoma U87G cells. Furthermore, DPT-Cog also decreased the growth of X-irradiated U87G senescent cells. In conclusion we characterized the DPT-Cog molecule, a new ApoE cog-mimetic and potential anti-tumor peptide. Our results clearly indicate that DPT-Cog counteracted PI3K survival pathways of U87G cells and is also toxic against irradiated U87G senescent cells.
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