title: PPP2R2C loss promotes castration-resistance and is associated with increased prostate cancer-specific mortality.
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 using signaling programs and growth factors that bypass canonical AR ligand-mediated mechanisms. We used an in vitro high-throughput RNA interference (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 downregulated in primary and metastatic prostate cancer, including two subunits of the protein phosphatase 2 (PP2A) holoenzyme complex: PPP2R1A, a structural subunit with known tumor-suppressor properties in several tumor types; and PPP2R2C, a PP2A substrate-binding regulatory subunit that has not been previously identified as a tumor suppressor. We show 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 promote growth independently of known AR-mediated transcriptional programs. Immunohistochemical 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 prostate cancers resist AR-pathway suppression and support inhibiting PPP2R2C complexes or the growth pathway(s) activated by PPP2R2C as a therapeutic strategy.
authors.affiliation: School of Medicine, University of Washington, Seattle, Washington, USA.
authors.forename: Eric G
authors.initials: EG
authors.lastname: Bluemn
authors.forename: Elysia Sophie
authors.initials: ES
authors.lastname: Spencer
authors.forename: Brigham
authors.initials: B
authors.lastname: Mecham
authors.forename: Ryan R
authors.initials: RR
authors.lastname: Gordon
authors.forename: Ilsa
authors.initials: I
authors.lastname: Coleman
authors.forename: Daniel
authors.initials: D
authors.lastname: Lewinshtein
authors.forename: Elahe
authors.initials: E
authors.lastname: Mostaghel
authors.forename: Xiaotun
authors.initials: X
authors.lastname: Zhang
authors.forename: James
authors.initials: J
authors.lastname: Annis
authors.forename: Carla
authors.initials: C
authors.lastname: Grandori
authors.forename: Christopher
authors.initials: C
authors.lastname: Porter
authors.forename: Peter S
authors.initials: PS
authors.lastname: Nelson
mesh_terms: D000728:Androgens / Q000172:deficiency; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D015536:Down-Regulation / Q000235:genetics; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D057166:High-Throughput Screening Assays; D006801:Humans; D008297:Male; D015999:Multivariate Analysis; D009362:Neoplasm Metastasis; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D064129:Prostatic Neoplasms, Castration-Resistant / Q000201:enzymology* / Q000235:genetics / Q000401:mortality* / Q000473:pathology; D054648:Protein Phosphatase 2 / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D011944:Receptors, Androgen / Q000378:metabolism; D012008:Recurrence; D015398:Signal Transduction; D016896:Treatment Outcome; D019061:src-Family Kinases / Q000378:metabolism
chemical_list: C410798:AR protein, human; D000728:Androgens; C517192:PPP2R2C protein, human; D034741:RNA, Small Interfering; D011944:Receptors, Androgen; D019869:Phosphatidylinositol 3-Kinases; D019061:src-Family Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D054648:Protein Phosphatase 2