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Inhibition of Pten deficient Castration Resistant Prostate Cancer by Targeting of the SET - PP2A Signaling axis.

dc.contributor.author Hu, X
dc.contributor.author Garcia, C
dc.contributor.author Fazli, L
dc.contributor.author Gleave, M
dc.contributor.author Vitek, MP
dc.contributor.author Jansen, M
dc.contributor.author Christensen, D
dc.contributor.author Mulholland, DJ
dc.coverage.spatial England
dc.date.accessioned 2018-02-01T16:00:53Z
dc.date.available 2018-02-01T16:00:53Z
dc.date.issued 2015-11-13
dc.identifier https://www.ncbi.nlm.nih.gov/pubmed/26563471
dc.identifier srep15182
dc.identifier.uri https://hdl.handle.net/10161/16047
dc.description.abstract The PP2A signaling axis regulates multiple oncogenic drivers of castration resistant prostate cancer (CRPC). We show that targeting the endogenous PP2A regulator, SET (I2PP2A), is a viable strategy to inhibit prostate cancers that are resistant to androgen deprivation therapy. Our data is corroborated by analysis of prostate cancer patient cohorts showing significant elevation of SET transcripts. Tissue microarray analysis reveals that elevated SET expression correlates with clinical cancer grading, duration of neoadjuvant hormone therapy (NHT) and time to biochemical recurrence. Using prostate regeneration assays, we show that in vivo SET overexpression is sufficient to induce hyperplasia and prostatic intraepithelial neoplasia. Knockdown of SET induced significant reductions in tumorgenesis both in murine and human xenograft models. To further validate SET as a therapeutic target, we conducted in vitro and in vivo treatments using OP449 - a recently characterized PP2A-activating drug (PAD). OP449 elicits robust anti-cancer effects inhibiting growth in a panel of enzalutamide resistant prostate cancer cell lines. Using the Pten conditional deletion mouse model of prostate cancer, OP449 potently inhibited PI3K-Akt signaling and impeded CRPC progression. Collectively, our data supports a critical role for the SET-PP2A signaling axis in CRPC progression and hormone resistant disease.
dc.language eng
dc.relation.ispartof Sci Rep
dc.relation.isversionof 10.1038/srep15182
dc.subject Animals
dc.subject Blotting, Western
dc.subject Cell Line, Tumor
dc.subject Cell Survival
dc.subject Dose-Response Relationship, Drug
dc.subject HEK293 Cells
dc.subject Histone Chaperones
dc.subject Humans
dc.subject Male
dc.subject Mice, Knockout
dc.subject Mice, Nude
dc.subject Mice, SCID
dc.subject Neoplasms, Experimental
dc.subject PTEN Phosphohydrolase
dc.subject Peptides
dc.subject Phosphatidylinositol 3-Kinases
dc.subject Prostatic Neoplasms, Castration-Resistant
dc.subject Protein Phosphatase 2
dc.subject Proto-Oncogene Proteins c-akt
dc.subject RNA Interference
dc.subject Reverse Transcriptase Polymerase Chain Reaction
dc.subject Signal Transduction
dc.subject Transcription Factors
dc.title Inhibition of Pten deficient Castration Resistant Prostate Cancer by Targeting of the SET - PP2A Signaling axis.
dc.type Journal article
pubs.author-url https://www.ncbi.nlm.nih.gov/pubmed/26563471
pubs.begin-page 15182
pubs.organisational-group Clinical Science Departments
pubs.organisational-group Duke
pubs.organisational-group Neurology
pubs.organisational-group Neurology, Behavioral Neurology
pubs.organisational-group School of Medicine
pubs.publication-status Published online
pubs.volume 5
dc.identifier.eissn 2045-2322


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