Inhibition of Pten deficient Castration Resistant Prostate Cancer by Targeting of the SET - PP2A Signaling axis.
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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.
Cell Line, Tumor
Dose-Response Relationship, Drug
Prostatic Neoplasms, Castration-Resistant
Protein Phosphatase 2
Proto-Oncogene Proteins c-akt
Reverse Transcriptase Polymerase Chain Reaction
Published Version (Please cite this version)10.1038/srep15182
Publication InfoHu, Xiaoyong; Garcia, Consuelo; Fazli, Ladan; Gleave, Martin; Vitek, Michael P; Jansen, Marilyn; ... Mulholland, David J (2015). Inhibition of Pten deficient Castration Resistant Prostate Cancer by Targeting of the SET - PP2A Signaling axis. Sci Rep, 5. pp. 15182. 10.1038/srep15182. Retrieved from https://hdl.handle.net/10161/16047.
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Adjunct Associate Professor in Neurology
The overall interest of my laboratory is to identify the underlying causes of neurodegenerative diseases such as Alzheimer's disease. Once causes or experimental endpoints are determined, then strategies to find chemicals which can ameliorate pathophysiological events can be devised. In general, we are working to create transgenic animals and validate them as models of human disease. Our specific approach has been to study the function of apolipoprotein-E (apoE) which