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
• AMP cyklický metabolismus   MeSH
• androgenní receptory metabolismus   MeSH
• androgeny farmakologie   MeSH
• cyklin-dependentní kinasa 2 metabolismus   MeSH
• cyklin-dependentní kinasy metabolismus   MeSH
• epitelové buňky účinky léků   enzymologie   patologie   MeSH
• imunohistochemie MeSH
• inhibitory proteinkinas farmakologie   MeSH
• kontrolní body buněčného cyklu účinky léků   MeSH
• lidé MeSH
• nádorové buněčné linie MeSH
• nádory prostaty patologie   MeSH
• neuroendokrinní buňky účinky léků   patologie   MeSH
• počet buněk MeSH
• proteinkinasa CDC2 MeSH
• signální transdukce účinky léků   MeSH
• transdiferenciace buněk * účinky léků   MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• AMP cyklický MeSH
• androgenní receptory MeSH
• androgeny MeSH
• CDK1 protein, human MeSH Prohlížeč
• CDK2 protein, human MeSH Prohlížeč
• cyklin-dependentní kinasa 2 MeSH
• cyklin-dependentní kinasy MeSH
• inhibitory proteinkinas MeSH
• proteinkinasa CDC2 MeSH