title: Disrupting the PIKE-A/Akt interaction inhibits glioblastoma cell survival, migration, invasion and colony formation.
abstract: The cyclin-dependent kinase 4 (CDK4) amplicon is frequently amplified in numerous human cancers including gliomas. PIKE-A, a proto-oncogene that is one of the important components of the CDK4 amplicon, binds to and enhances the kinase activity of Akt, thereby promoting cancer progression. To define the roles of the PIKE-A/Akt interaction in glioblastoma multiform (GBM) progression, we used biochemical protein/protein interaction (PPI) assays and live cell fluorescence-based protein complementation assays to search for small peptide antagonist from these proteins that were able to block their interaction. Here, we show that disruption of the interaction between PIKE-A and Akt by the small peptides significantly reduces glioblastoma cell proliferation, colony formation, migration and invasion. Disruption of PIKE-A/Akt association potently suppressed GBM cell proliferation and sensitized the cells to two clinical drugs that are currently used to treat GBM. Interestingly, GBM cells containing the CDK4 amplicon were more responsive to the inhibition of the PIKE-A/Akt interaction than GBM cells lacking this amplicon. Taken together, our findings provide proof-of-principle that blocking a PPI that is essential for cancer progression provides a valuable strategy for therapeutic discovery.
authors.affiliation: Department of Pathology and Laboratory Medicine, Emory University, Atlanta, GA 30300, USA.
authors.forename: Q
authors.initials: Q
authors.lastname: Qi
authors.forename: K
authors.initials: K
authors.lastname: He
authors.forename: X
authors.initials: X
authors.lastname: Liu
authors.forename: C
authors.initials: C
authors.lastname: Pham
authors.forename: C
authors.initials: C
authors.lastname: Meyerkord
authors.forename: H
authors.initials: H
authors.lastname: Fu
authors.forename: K
authors.initials: K
authors.lastname: Ye
mesh_terms: D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D019204:GTP-Binding Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D020690:GTPase-Activating Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D005909:Glioblastoma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D057809:HEK293 Cells; D006801:Humans; D008969:Molecular Sequence Data; D009361:Neoplasm Invasiveness; D010455:Peptides / Q000494:pharmacology*; D010766:Phosphorylation; D054730:Protein Interaction Domains and Motifs; D000090063:Proto-Oncogene Mas; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014162:Transfection
chemical_list: D020690:GTPase-Activating Proteins; C000715470:MAS1 protein, human; D010455:Peptides; D000090063:Proto-Oncogene Mas; D051057:Proto-Oncogene Proteins c-akt; C485997:AGAP2 protein, human; D019204:GTP-Binding Proteins