CIP2A is a candidate therapeutic target in clinically challenging prostate cancer cell populations

Oncotarget. 2015 Aug 14;6(23):19661-70. doi: 10.18632/oncotarget.3875.

Abstract

Residual androgen receptor (AR)-signaling and presence of cancer stem-like cells (SCs) are the two emerging paradigms for clinically challenging castration-resistant prostate cancer (CRPC). Therefore, identification of AR-target proteins that are also overexpressed in the cancer SC population would be an attractive therapeutic approach.Our analysis of over three hundred clinical samples and patient-derived prostate epithelial cultures (PPECs), revealed Cancerous inhibitor of protein phosphatase 2A (CIP2A) as one such target. CIP2A is significantly overexpressed in both hormone-naïve prostate cancer (HN-PC) and CRPC patients . CIP2A is also overexpressed, by 3- and 30-fold, in HN-PC and CRPC SCs respectively. In vivo binding of the AR to the intronic region of CIP2A and its functionality in the AR-moderate and AR-high expressing LNCaP cell-model systems is also demonstrated. Further, we show that AR positively regulates CIP2A expression, both at the mRNA and protein level. Finally, CIP2A depletion reduced cell viability and colony forming efficiency of AR-independent PPECs as well as AR-responsive LNCaP cells, in which anchorage-independent growth is also impaired.These findings identify CIP2A as a common denominator for AR-signaling and cancer SC functionality, highlighting its potential therapeutic significance in the most clinically challenging prostate pathology: castration-resistant prostate cancer.

Keywords: CIP2A; androgen receptor; cancer stem-like cells; castration-resistant prostate cancer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Androgen Antagonists / pharmacology
  • Antineoplastic Agents, Hormonal / pharmacology
  • Autoantigens / genetics
  • Autoantigens / metabolism*
  • Binding Sites
  • Cell Line, Tumor
  • Cell Proliferation
  • Cell Survival
  • Gene Expression Regulation, Neoplastic
  • Genetic Therapy / methods
  • Humans
  • Intracellular Signaling Peptides and Proteins
  • Introns
  • Male
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism*
  • Molecular Targeted Therapy
  • Neoplastic Stem Cells / drug effects
  • Neoplastic Stem Cells / metabolism*
  • Neoplastic Stem Cells / pathology
  • Prostatic Neoplasms, Castration-Resistant / genetics
  • Prostatic Neoplasms, Castration-Resistant / metabolism*
  • Prostatic Neoplasms, Castration-Resistant / pathology
  • Prostatic Neoplasms, Castration-Resistant / therapy*
  • Protein Binding
  • RNA Interference
  • RNA, Messenger / metabolism
  • Receptors, Androgen / drug effects
  • Receptors, Androgen / metabolism
  • Signal Transduction
  • Time Factors
  • Transcription, Genetic
  • Transfection
  • Tumor Cells, Cultured
  • Up-Regulation

Substances

  • AR protein, human
  • Androgen Antagonists
  • Antineoplastic Agents, Hormonal
  • Autoantigens
  • CIP2A protein, human
  • Intracellular Signaling Peptides and Proteins
  • Membrane Proteins
  • RNA, Messenger
  • Receptors, Androgen