title: The role of high cell density in the promotion of neuroendocrine transdifferentiation of prostate cancer cells.
abstract: 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.
authors.forename: Zuzana
authors.initials: Z
authors.lastname: Pernicová
authors.forename: Eva
authors.initials: E
authors.lastname: Slabáková
authors.forename: Radek
authors.initials: R
authors.lastname: Fedr
authors.forename: Šárka
authors.initials: Š
authors.lastname: Šimečková
authors.forename: Josef
authors.initials: J
authors.lastname: Jaroš
authors.forename: Tereza
authors.initials: T
authors.lastname: Suchánková
authors.forename: Jan
authors.initials: J
authors.lastname: Bouchal
authors.forename: Gvantsa
authors.initials: G
authors.lastname: Kharaishvili
authors.forename: Milan
authors.initials: M
authors.lastname: Král
authors.forename: Alois
authors.initials: A
authors.lastname: Kozubík
authors.affiliation: Department of Cytokinetics, Institute of Biophysics, Academy of Sciences of the Czech Republic, v,v,i, Královopolská 135, CZ-612 65 Brno, Czech Republic. ksoucek@ibp.cz.
authors.forename: Karel
authors.initials: K
authors.lastname: Souček
mesh_terms: D000728:Androgens / Q000494:pharmacology; D016203:CDC2 Protein Kinase; D002452:Cell Count; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D054338:Cell Transdifferentiation / Q000187:drug effects; D000242:Cyclic AMP / Q000378:metabolism; D051357:Cyclin-Dependent Kinase 2 / Q000378:metabolism; D018844:Cyclin-Dependent Kinases / Q000378:metabolism; D004847:Epithelial Cells / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D055099:Neuroendocrine Cells / Q000187:drug effects / Q000473:pathology*; D011471:Prostatic Neoplasms / Q000473:pathology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011944:Receptors, Androgen / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D000728:Androgens; D047428:Protein Kinase Inhibitors; D011944:Receptors, Androgen; D000242:Cyclic AMP; D016203:CDC2 Protein Kinase; C528899:CDK1 protein, human; C495894:CDK2 protein, human; D051357:Cyclin-Dependent Kinase 2; D018844:Cyclin-Dependent Kinases