BACKGROUND: Tumor heterogeneity and the plasticity of cancer cells present challenges for effective clinical diagnosis and therapy. Such challenges are epitomized by neuroendocrine transdifferentiation (NED) and the emergence of neuroendocrine-like cancer cells in prostate tumors. This phenomenon frequently arises from androgen-depleted prostate adenocarcinoma and is associated with the development of castration-resistant prostate cancer and poor prognosis. RESULTS: In this study, we showed that NED was evoked in both androgen receptor (AR)-positive and AR-negative prostate epithelial cell lines by growing the cells to a high density. Androgen depletion and high-density cultivation were both associated with cell cycle arrest and deregulated expression of several cell cycle regulators, such as p27Kip1, members of the cyclin D protein family, and Cdk2. Dual inhibition of Cdk1 and Cdk2 using pharmacological inhibitor or RNAi led to modulation of the cell cycle and promotion of NED. We further demonstrated that the cyclic adenosine 3', 5'-monophosphate (cAMP)-mediated pathway is activated in the high-density conditions. Importantly, inhibition of cAMP signaling using a specific inhibitor of adenylate cyclase, MDL-12330A, abolished the promotion of NED by high cell density. CONCLUSIONS: Taken together, our results imply a new relationship between cell cycle attenuation and promotion of NED and suggest high cell density as a trigger for cAMP signaling that can mediate reversible NED in prostate cancer cells.

• MeSH
• Cyclic AMP metabolism   MeSH
• Receptors, Androgen metabolism   MeSH
• Androgens pharmacology   MeSH
• Cyclin-Dependent Kinase 2 metabolism   MeSH
• Cyclin-Dependent Kinases metabolism   MeSH
• Epithelial Cells drug effects   enzymology   pathology   MeSH
• Immunohistochemistry MeSH
• Protein Kinase Inhibitors pharmacology   MeSH
• Cell Cycle Checkpoints drug effects   MeSH
• Humans MeSH
• Cell Line, Tumor MeSH
• Prostatic Neoplasms pathology   MeSH
• Neuroendocrine Cells drug effects   pathology   MeSH
• Cell Count MeSH
• CDC2 Protein Kinase MeSH
• Signal Transduction drug effects   MeSH
• Cell Transdifferentiation * drug effects   MeSH
• Check Tag
• Humans MeSH
• Male MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Cyclic AMP MeSH
• Receptors, Androgen MeSH
• Androgens MeSH
• CDK1 protein, human MeSH Browser
• CDK2 protein, human MeSH Browser
• Cyclin-Dependent Kinase 2 MeSH
• Cyclin-Dependent Kinases MeSH
• Protein Kinase Inhibitors MeSH
• CDC2 Protein Kinase MeSH

Although the induction of senescence in cancer cells is a potent mechanism of tumor suppression, senescent cells remain metabolically active and may secrete a broad spectrum of factors that promote tumorigenicity in neighboring malignant cells. Here we show that androgen deprivation therapy (ADT), a widely used treatment for advanced prostate cancer, induces a senescence-associated secretory phenotype in prostate cancer epithelial cells, indicated by increases in senescence-associated β-galactosidase activity, heterochromatin protein 1β foci, and expression of cathepsin B and insulin-like growth factor binding protein 3. Interestingly, ADT also induced high levels of vimentin expression in prostate cancer cell lines in vitro and in human prostate tumors in vivo. The induction of the senescence-associated secretory phenotype by androgen depletion was mediated, at least in part, by down-regulation of S-phase kinase-associated protein 2, whereas the neuroendocrine differentiation of prostate cancer cells was under separate control. These data demonstrate a previously unrecognized link between inhibition of androgen receptor signaling, down-regulation of S-phase kinase-associated protein 2, and the appearance of secretory, tumor-promoting senescent cells in prostate tumors. We propose that ADT may contribute to the development of androgen-independent prostate cancer through modulation of the tissue microenvironment by senescent cells.

• MeSH
• Receptors, Androgen metabolism   MeSH
• Androgen Antagonists pharmacology   MeSH
• beta-Galactosidase metabolism   MeSH
• Down-Regulation drug effects   MeSH
• PTEN Phosphohydrolase metabolism   MeSH
• Insulin-Like Growth Factor Binding Protein 3 metabolism   MeSH
• Cathepsin B metabolism   MeSH
• Microscopy, Confocal MeSH
• Humans MeSH
• Cell Line, Tumor MeSH
• Prostatic Neoplasms genetics   metabolism   pathology   MeSH
• S-Phase Kinase-Associated Proteins genetics   metabolism   MeSH
• Flow Cytometry MeSH
• RNA Interference MeSH
• Signal Transduction drug effects   MeSH
• Cellular Senescence drug effects   MeSH
• Vimentin metabolism   MeSH
• Blotting, Western MeSH
• Check Tag
• Humans MeSH
• Male MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Receptors, Androgen MeSH
• Androgen Antagonists MeSH
• AR protein, human MeSH Browser
• beta-Galactosidase MeSH
• PTEN Phosphohydrolase MeSH
• Insulin-Like Growth Factor Binding Protein 3 MeSH
• Cathepsin B MeSH
• S-Phase Kinase-Associated Proteins MeSH
• Vimentin MeSH