PPP2R2C loss promotes castration-resistant prostate cancer growth and is associated with increased prostate cancer-specific mortality
Bluemn EG, Spencer ES, Mecham B, Gordon RR, Coleman I, Lewinshtein D, Mostaghel E, Zhang X, Annis J, Grandori C, Porter C, Nelson PS. Mol Cancer Res. 2013 Mar 14. [Epub ahead of print]

Source

Fred Hutchinson Cancer Research Center.

Abstract

Metastatic prostate cancers generally rely on androgen receptor (AR) signaling for growth and survival, even following systemic androgen deprivation therapy (ADT). However, recent evidence suggests that some advanced prostate cancers escape ADT by utilizing signaling pro-grams and growth factors that bypass canonical AR ligand-mediated mechanisms. We utilized an in vitro high-throughput RNAi screen to identify pathways in androgen-dependent prostate cancer cell lines whose loss of function promotes androgen ligand-independent growth. We identified 40 genes where knockdown promoted proliferation of both LNCaP and VCaP prostate cancer cells in the absence of androgen. Of these, 14 were down-regulated in primary and metastatic prostate cancer, including two subunits of the protein phosphatase 2 (PP2A) holoen-zyme complex: PPP2R1A, a structural subunit with known tumor-suppressor properties in sev-eral tumor types; and PPP2R2C, a PP2A substrate-binding regulatory subunit that has not been previously identified as a tumor suppressor. We demonstrate that loss of PPP2R2C promotes androgen ligand depletion-resistant prostate cancer growth without altering AR expression or canonical AR-regulated gene expression. Furthermore, cell proliferation induced by PPP2R2C loss was not inhibited by the AR antagonist MDV3100, indicating that PPP2R2C loss may pro-mote growth independently of known AR-mediated transcriptional programs. Immunohisto-chemical analysis of PPP2R2C protein levels in primary prostate tumors determined that low PPP2R2C expression significantly associated with an increased likelihood of cancer recurrence and cancer-specific mortality. These findings provide insights into mechanisms by which pros-tate cancers resist AR-pathway suppression, and support inhibiting PPP2R2C complexes or the growth pathway(s) activated by PPP2R2C as a therapeutic strategy.