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

Hu, Xiaoyong; Garcia, Consuelo; Fazli, Ladan; Gleave, Martin; Vitek, Michael P; Jansen, Marilyn; Christensen, Dale; Mulholland, David J

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

dc.contributor.author	Hu, Xiaoyong
dc.contributor.author	Garcia, Consuelo
dc.contributor.author	Fazli, Ladan
dc.contributor.author	Gleave, Martin
dc.contributor.author	Vitek, Michael P
dc.contributor.author	Jansen, Marilyn
dc.contributor.author	Christensen, Dale
dc.contributor.author	Mulholland, David J
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.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.identifier	https://www.ncbi.nlm.nih.gov/pubmed/26563471
dc.identifier	srep15182
dc.identifier.eissn	2045-2322
dc.identifier.uri	https://hdl.handle.net/10161/16047
dc.language	eng
dc.publisher	Springer Science and Business Media LLC
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
duke.contributor.orcid	Vitek, Michael P\|0000-0001-8140-8048
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

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