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.
Highlights
Prostate cancer is driven by multiple oncogenic pathways including heightened expression of PI3K-Akt signaling which is observed in at least 90% of advanced prostate cancers[1]
Using the recently described SET antagonist peptide, OP449, which has been reported to activate Phosphatase 2A (PP2A) in multiple cancer cell types and inhibit relevant oncogenic pathways including c-Myc and Akt[13,17,18,19,20,21], we found that pharmacological inactivation of SET resulted in potent growth inhibition of enzalutamide resistant prostate cancers
Since PP2A expression is reduced in multiple cancers, we investigated the expression profile of the PP2A inhibitor, SET, in prostate cancer progression
Summary
Prostate cancer is driven by multiple oncogenic pathways including heightened expression of PI3K-Akt signaling which is observed in at least 90% of advanced prostate cancers[1]. Several endogenous inhibitors of PP2A have been identified including Cellular Inhibitor of PP2A (CIP2A)[4] and SET ( known as I2PP2A)[5,6] Both oncogene proteins are direct regulators of PP2A and, are predicted to regulate cancer progression in multiple tissue types. Using the recently described SET antagonist peptide, OP449, which has been reported to activate PP2A in multiple cancer cell types and inhibit relevant oncogenic pathways including c-Myc and Akt[13,17,18,19,20,21], we found that pharmacological inactivation of SET resulted in potent growth inhibition of enzalutamide resistant prostate cancers. Our data constitute proof of principle that SET-PP2A signaling axis is a viable target for prostate cancers that may be otherwise poorly responsive to standard of care treatments
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