Multipathways for transdifferentiation of human prostate cancer cells into neuroendocrine-like phenotype

Biochim Biophys Acta. 2001 May 28;1539(1-2):28-43. doi: 10.1016/s0167-4889(01)00087-8.


The neuroendocrine (NE) cell is a minor cell population in normal human prostate glands. The number of NE cells is increased in advanced hormone-refractory prostate carcinomas (PCA). The mechanism of increased NE cell population in these advanced tumors is poorly understood. We examined molecular mechanisms which may be involved in the regulation of the transdifferentiation process of human PCA cells leading to a NE phenotype. We compared PCA cell lines LNCaP and PC-3 in the following medium conditions: steroid-reduced (SR), interleukin-6 (IL-6)-supplemented, or dibutyrate cAMP (db-cAMP)-supplemented. We found that androgen-responsive C-33 LNCaP cells responded to all treatments, having a neuronal-like morphology. In contrast, C-81 LNCaP cells, having a decreased androgen responsiveness, had a less pronounced effect although followed a similar trend. Androgen-unresponsive PC-3 cells showed little change in their morphology. Grown in the SR condition, the level of neuron-specific enolase (NSE), a marker of neuronal cells, was upregulated in C-33 LNCaP cells, while to a lesser degree in the presence of IL-6. In the presence of db-cAMP, the NSE level in C-33 cells was decreased, lower than that in control cells. An opposite effect was observed for C-81 LNCaP cells. Nevertheless, the NSE level was only elevated in db-cAMP-treated PC-3 cells, but no change was found in PC-3 cells grown in the SR- or IL-6-supplemented medium. Thus, a similar gross phenotypic change may correlate with differential molecular expressions. We also analyzed the expression of protein tyrosine phosphatase alpha (RPTPalpha) since it plays a critical role in normal neuronal differentiation and signaling. Our results showed that the expression of RPTPalpha correlates with the NE phenotypic change of LNCaP cells in the SR condition. In summary, our data clearly show that the molecular process by which cultured human prostate cancer cells undergo a transdifferentiation process to a NE cell-like phenotype is accompanied by differential expressions of different markers, and a gross NE cell-like phenotype can occur by exposing PCA cells to different pharmacological agents.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Androgens / deficiency
  • Bucladesine / pharmacology
  • Carcinoma / etiology
  • Carcinoma / pathology*
  • Cell Differentiation / drug effects
  • Culture Media
  • Humans
  • Hydroxamic Acids / pharmacology
  • Interleukin-6 / pharmacology
  • Male
  • Neurosecretory Systems / drug effects
  • Neurosecretory Systems / pathology
  • Phenotype
  • Phosphopyruvate Hydratase / analysis
  • Prostate-Specific Antigen / analysis
  • Prostatic Neoplasms / etiology
  • Prostatic Neoplasms / pathology*
  • Protein Tyrosine Phosphatases / analysis
  • Receptor-Like Protein Tyrosine Phosphatases, Class 4
  • Receptors, Androgen / analysis
  • Receptors, Cell Surface*
  • Staining and Labeling
  • Tumor Cells, Cultured / drug effects*


  • Androgens
  • Culture Media
  • Hydroxamic Acids
  • Interleukin-6
  • Receptors, Androgen
  • Receptors, Cell Surface
  • trichostatin A
  • Bucladesine
  • PTPRA protein, human
  • Protein Tyrosine Phosphatases
  • Receptor-Like Protein Tyrosine Phosphatases, Class 4
  • Prostate-Specific Antigen
  • Phosphopyruvate Hydratase