Multipathways for transdifferentiation of human prostate cancer cells intoneuroendocrine-like phenotype

The neuroendocrine (NE) cell is a minor cell population in normal human pro state glands. The number of NE eels is increased in advanced hormone-refrac tory prostate carcinomas (PCA). The mechanism of increased NE cell populati on in these advanced tumors is poorly understood. We examined molecular mec hanisms 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)-supple mented, We found that androgen-responsive C-33 LNCaP cells responded to all treatments, having a neuronal-like morphology. In contrast, C-81 LNCaP cel ls, having a decreased androgen responsiveness, had a less pronounced effec t although followed a similar trend, Androgen-unresponsive PC-3 cells showe d little change in their morphology, Grown in the SR condition, the level o f neuron-specific enolase (NSE), a marker of neuronal cells, was upregulate d 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-sup plemented medium. Thus, a similar gross phenotypic change may correlate wit h differential molecular expressions. We also analyzed the expression of pr otein tyrosine phosphatase alpha (RPTP alpha) since it plays a critical rol e in normal neuronal differentiation and signaling. Our results showed that the expression of RPTP alpha correlates with the NE phenotypic change of L NCaP cells in the SR condition, In summary, our data clearly show that the molecular process by which cultured human prostate cancer cells undergo a t ransdifferentiation process to a NE cell-like phenotype is accompanied by d ifferential expressions of different markers, and a gross NE cell-like phen otype can occur by exposing PCA cells to different pharmacological agents, (C) 2001 Elsevier Science B,V, All rights reserved.