TERMINAL NEUROENDOCRINE DIFFERENTIATION OF HUMAN PROSTATE CARCINOMA-CELLS IN RESPONSE TO INCREASED INTRACELLULAR CYCLIC-AMP

Recent clinicopathologic studies have shown that many prostatic adenoc arcinomas express focal neuroendocrine differentiation and that neuroe ndocrine differentiation is most apparent in advanced anaplastic tumor s. While studying growth-regulatory signal transduction events in huma n prostate carcinoma cell lines, we found that in two of four cell lin es, the androgen-sensitive line LNCaP and the highly metastatic androg en-independent line PC-3-M, elevation of cAMP through addition of cAMP analogues or phosphodiesterase inhibitors induced a markedly neuronal morphology. Also in LNCaP cells ultrastructural analysis showed that cAMP induced the appearance of neurosecretory cell-like dense-core gra nules. Phenotypic analysis of untreated LNCaP and PC 3-M cells showed that both cell lines express markers of the neural crest including S-1 00, chromogranin A, pp60(c-src), and neuron-specific enolase as well a s the epithelial marker KS1/4 and stage-specific embryonic antigen 4. In PC-3-M tells, cAMP markedly elevated neuron-specific enolase protei n and caused an increase in the specific activity of the neuroendocrin e marker pp60(c-src), and in both cell lines expression of KS1/4 and s tage specific embryonic antigen 4 was down-regulated. In addition to e ffects on lineage markers, cAMP treatment induced G(1) synchronization , growth arrest, and loss of clonogenicity, indicating terminal differ entiation. Our data provide direct evidence of plasticity in the linea ge commitment of adenocarcinoma of the prostate. We have shown that ce ll-permeant cAMP analogues can induce terminal differentiation, sugges ting that hydrolysis-resistant cyclic nucleotides may present an addit ional approach to the treatment of advanced prostate cancer.