Cell cycle regulator cdk2ap1 inhibits prostate cancer cell growth and modifies androgen-responsive pathway function

Prostate. 2009 Oct 1;69(14):1586-97. doi: 10.1002/pros.21007.


Background: We evaluated the effect of expressing the cell cycle regulator cdk2ap1, downregulated in prostate cancer cell lines, in inhibiting prostate cancer cell growth.

Methods: Expression of cdk2ap1 using a tet-inducible lentiviral system modified growth rate, induced cell cycle arrest and apoptosis and reduced the invasive ability of prostate cancer cell lines, as assayed by cell viability, cell cycle profiling, Caspase 3/7 detection, and matrigel invasion assays. We examined the effect of expressing cdk2ap1 on gene expression profiles of cytokine, invasion, apoptotic, and androgen response pathways using quantitative real-time PCR, and used androgen-responsive reporter gene assays, and methylation-sensitive PCR to examine the mechanism of cdk2ap1 interaction with androgen-responsive pathways.

Results: The expression of cdk2ap1 correlated with a reduction in cellular growth, irrespective of inhibition or stimulation of androgen receptor (AR) signaling pathways. Cell cycle arrest, increased apoptosis, and a reduction in invasiveness phenotypes were observed upon cdk2ap1 expression. Enhanced demethylation at the AR promoter, AR expression increases, and enhanced AR transcriptional activity correlated with cdk2ap1 expression.

Conclusions: Our findings support a novel concept by which cell cycle inhibitor genes can impact prostate cancer phenotypes by restoring a tumor suppressive function to androgen-responsive pathways and this function may involve modulation of a subset of functions of the AR.

MeSH terms

  • Androgens / metabolism*
  • Apoptosis / physiology
  • Caspase 3 / metabolism
  • Caspase 7 / metabolism
  • Cell Division / physiology
  • Cell Line, Tumor
  • Cell Survival / physiology
  • Down-Regulation / physiology
  • Epigenesis, Genetic / physiology
  • Gene Expression Regulation, Neoplastic / physiology
  • Humans
  • Male
  • Neoplasm Invasiveness / pathology
  • Neoplasm Invasiveness / physiopathology
  • Prostatic Neoplasms / metabolism
  • Prostatic Neoplasms / pathology*
  • Prostatic Neoplasms / physiopathology*
  • Receptors, Androgen / genetics
  • Receptors, Androgen / metabolism
  • Signal Transduction / physiology
  • Transcription, Genetic / physiology
  • Tumor Suppressor Proteins / genetics*
  • Tumor Suppressor Proteins / metabolism*


  • Androgens
  • CDK2AP1 protein, human
  • Receptors, Androgen
  • Tumor Suppressor Proteins
  • Caspase 3
  • Caspase 7