Neuroendocrine transdifferentiation induced by VPA is mediated by PPARgamma activation and confers resistance to antiblastic therapy in prostate carcinoma

Prostate. 2008 May 1;68(6):588-98. doi: 10.1002/pros.20708.


Background: Prostate cancer (PCa) is the most commonly diagnosed cancer in men in the Western Countries. When prostatectomy fails to eradicate the primary tumor, PCa is generally refractory to all therapeutic approaches. Valproic acid (VPA) is a promising anticancer agent recently assigned to the class of histone deacetylase (HDAC) inhibitors. However molecular mechanisms underlying VPA action in PCa cells are largely unknown and further experimental validation to prove its potential application in clinic practice is needed.

Results: In our study we show that VPA is a potent inducer of neuro-endocrine transdifferentiation (NET) in androgen receptor null PCa cells, both in vitro and in vivo. NET was an early event detectable through the expression of neuro-endocrine (NE) markers within 72 hr after VPA treatment and it was associated to a reduction in the overall cell proliferation. When we interrupted VPA treatment we observed the recovery in residual cells of the basal proliferation rate both in vitro and in a xenograft model. The NET process was related to Bcl-2 over-expression in non-NE PCa cells and to the activation of PPARgamma in NE cells. The use of specific PPARgamma antagonist was able to reduce significantly the expression of NE markers induced by VPA.

Conclusions: Our data indicate that the use of VPA as monotherapy in PCa has to be considered with extreme caution, since it may induce an unfavorable NET. In order to counteract the VPA-induced NET, the inhibition of PPARgamma may represent a suitable adjuvant treatment strategy and awaits further experimental validation.

MeSH terms

  • Adenocarcinoma / drug therapy*
  • Adenocarcinoma / metabolism
  • Adenocarcinoma / pathology
  • Anilides / pharmacology
  • Animals
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cell Transdifferentiation / drug effects*
  • Cell Transdifferentiation / physiology
  • Cell Transformation, Neoplastic / drug effects
  • Cell Transformation, Neoplastic / pathology
  • Drug Combinations
  • Enzyme Inhibitors / pharmacology*
  • Histone Deacetylase Inhibitors
  • Humans
  • Male
  • Mice
  • Mice, Nude
  • Neurosecretory Systems / drug effects*
  • Neurosecretory Systems / pathology
  • PPAR gamma / antagonists & inhibitors
  • PPAR gamma / metabolism*
  • Prostatic Neoplasms / drug therapy*
  • Prostatic Neoplasms / metabolism
  • Prostatic Neoplasms / pathology
  • Proto-Oncogene Proteins c-bcl-2 / metabolism
  • Valproic Acid / pharmacology*
  • Xenograft Model Antitumor Assays


  • 2-chloro-5-nitrobenzanilide
  • Anilides
  • Drug Combinations
  • Enzyme Inhibitors
  • Histone Deacetylase Inhibitors
  • PPAR gamma
  • Proto-Oncogene Proteins c-bcl-2
  • Valproic Acid