PPP2R2C loss promotes castration-resistance and is associated with increased prostate cancer-specific mortality

Eric G. Bluemn, Elysia Sophie Spencer, Brigham Mecham, Ryan Gordon, Ilsa Coleman, Daniel Lewinshtein, Elahe Mostaghel, Xiaotun Zhang, James Annis, Carla Grandori, Christopher Porter, Peter S. Nelson

Research output: Contribution to journalArticle

22 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)568-578
Number of pages11
JournalMolecular Cancer Research
Volume11
Issue number6
DOIs
StatePublished - Jun 2013
Externally publishedYes

Fingerprint

Castration
Androgen Receptors
Prostatic Neoplasms
Androgens
Mortality
Growth
Neoplasms
Ligands
Androgen Receptor Antagonists
Gene Knockdown Techniques
Protein Phosphatase 2
Holoenzymes
RNA Interference
Prostate
Intercellular Signaling Peptides and Proteins
Therapeutics
Down-Regulation
Cell Proliferation
Gene Expression
Recurrence

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Oncology

Cite this

PPP2R2C loss promotes castration-resistance and is associated with increased prostate cancer-specific mortality. / Bluemn, Eric G.; Spencer, Elysia Sophie; Mecham, Brigham; Gordon, Ryan; Coleman, Ilsa; Lewinshtein, Daniel; Mostaghel, Elahe; Zhang, Xiaotun; Annis, James; Grandori, Carla; Porter, Christopher; Nelson, Peter S.

In: Molecular Cancer Research, Vol. 11, No. 6, 06.2013, p. 568-578.

Research output: Contribution to journalArticle

Bluemn, EG, Spencer, ES, Mecham, B, Gordon, R, Coleman, I, Lewinshtein, D, Mostaghel, E, Zhang, X, Annis, J, Grandori, C, Porter, C & Nelson, PS 2013, 'PPP2R2C loss promotes castration-resistance and is associated with increased prostate cancer-specific mortality', Molecular Cancer Research, vol. 11, no. 6, pp. 568-578. https://doi.org/10.1158/1541-7786.MCR-12-0710
Bluemn, Eric G. ; Spencer, Elysia Sophie ; Mecham, Brigham ; Gordon, Ryan ; Coleman, Ilsa ; Lewinshtein, Daniel ; Mostaghel, Elahe ; Zhang, Xiaotun ; Annis, James ; Grandori, Carla ; Porter, Christopher ; Nelson, Peter S. / PPP2R2C loss promotes castration-resistance and is associated with increased prostate cancer-specific mortality. In: Molecular Cancer Research. 2013 ; Vol. 11, No. 6. pp. 568-578.
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AU - Spencer, Elysia Sophie

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AU - Gordon, Ryan

AU - Coleman, Ilsa

AU - Lewinshtein, Daniel

AU - Mostaghel, Elahe

AU - Zhang, Xiaotun

AU - Annis, James

AU - Grandori, Carla

AU - Porter, Christopher

AU - Nelson, Peter S.

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