title: Terminal neuroendocrine differentiation of human prostate carcinoma cells in response to increased intracellular cyclic AMP.
abstract: Recent clinicopathologic studies have shown that many prostatic adenocarcinomas express focal neuroendocrine differentiation and that neuroendocrine differentiation is most apparent in advanced anaplastic tumors. While studying growth-regulatory signal transduction events in human prostate carcinoma cell lines, we found that in two of four cell lines, the androgen-sensitive line LNCaP and the highly metastatic androgen-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 granules. Phenotypic analysis of untreated LNCaP and PC-3-M cells showed that both cell lines express markers of the neural crest including S-100, chromogranin A, pp60c-src, and neuron-specific enolase as well as the epithelial marker KS1/4 and stage-specific embryonic antigen 4. In PC-3-M cells, cAMP markedly elevated neuron-specific enolase protein and caused an increase in the specific activity of the neuroendocrine marker pp60c-src, and in both cell lines expression of KS1/4 and stage-specific embryonic antigen 4 was down-regulated. In addition to effects on lineage markers, cAMP treatment induced G1 synchronization, growth arrest, and loss of clonogenicity, indicating terminal differentiation. Our data provide direct evidence of plasticity in the lineage commitment of adenocarcinoma of the prostate. We have shown that cell-permeant cAMP analogues can induce terminal differentiation, suggesting that hydrolysis-resistant cyclic nucleotides may present an additional approach to the treatment of advanced prostate cancer.
authors.affiliation: Clinical Pharmacology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892.
authors.forename: Y J
authors.initials: YJ
authors.lastname: Bang
authors.forename: F
authors.initials: F
authors.lastname: Pirnia
authors.forename: W G
authors.initials: WG
authors.lastname: Fang
authors.forename: W K
authors.initials: WK
authors.lastname: Kang
authors.forename: O
authors.initials: O
authors.lastname: Sartor
authors.forename: L
authors.initials: L
authors.lastname: Whitesell
authors.forename: M J
authors.initials: MJ
authors.lastname: Ha
authors.forename: M
authors.initials: M
authors.lastname: Tsokos
authors.forename: M D
authors.initials: MD
authors.lastname: Sheahan
authors.forename: P
authors.initials: P
authors.lastname: Nguyen
authors.forename: W T
authors.initials: WT
authors.lastname: Niklinski
authors.forename: C E
authors.initials: CE
authors.lastname: Myers
authors.forename: J B
authors.initials: JB
authors.lastname: Trepel
mesh_terms: D000230:Adenocarcinoma / Q000473:pathology*; D002454:Cell Differentiation; D002455:Cell Division; D002460:Cell Line; D053379:Chromogranin A; D002864:Chromogranins / Q000378:metabolism; D000242:Cyclic AMP / Q000502:physiology*; D003593:Cytoplasm / Q000502:physiology; D004702:Endocrine Glands / Q000166:cytology; D004847:Epithelial Cells; D006801:Humans; D008297:Male; D009474:Neurons / Q000166:cytology; D010751:Phosphopyruvate Hydratase / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000473:pathology*; D009418:S100 Proteins / Q000378:metabolism
chemical_list: D053379:Chromogranin A; D002864:Chromogranins; D009418:S100 Proteins; D000242:Cyclic AMP; D010751:Phosphopyruvate Hydratase