title: Notch signaling modulates hypoxia-induced neuroendocrine differentiation of human prostate cancer cells.
abstract: Prostate carcinoma is among the most common causes of cancer-related death in men, representing 15% of all male malignancies in developed countries. Neuroendocrine differentiation (NED) has been associated with tumor progression, poor prognosis, and with the androgen-independent status. Currently, no successful therapy exists for advanced, castration-resistant disease. Because hypoxia has been linked to prostate cancer progression and unfavorable outcome, we sought to determine whether hypoxia would impact the degree of neuroendocrine differentiation of prostate cancer cells in vitro.
  
  
  RESULTS
  Exposure of LNCaP cells to low oxygen tension induced a neuroendocrine phenotype, associated with an increased expression of the transcription factor neurogenin3 and neuroendocrine markers, such as neuron-specific enolase, chromogranin A, and β3-tubulin. Moreover, hypoxia triggered a significant decrease of Notch 1 and Notch 2 mRNA and protein expression, with subsequent downregulation of Notch-mediated signaling, as shown by reduced levels of the Notch target genes, Hes1 and Hey1. NED was promoted by attenuation of Hes1 transcription, as cells expressing a dominant-negative form of Hes1 displayed increased levels of neuroendocrine markers under normoxic conditions. Although hypoxia downregulated Notch 1 and Notch 2 mRNA transcription and receptor activation also in the androgen-independent cell lines, PC-3 and Du145, it did not change the extent of NED in these cultures, suggesting that androgen sensitivity may be required for transdifferentiation to occur.
  
  
  CONCLUSIONS
  Hypoxia induces NED of LNCaP cells in vitro, which seems to be driven by the inhibition of Notch signaling with subsequent downregulation of Hes1 transcription.
authors.affiliation: Department of Clinical Physiopathology, University of Florence, Florence, Italy.
authors.forename: Giovanna
authors.initials: G
authors.lastname: Danza
authors.forename: Claudia
authors.initials: C
authors.lastname: Di Serio
authors.forename: Fabiana
authors.initials: F
authors.lastname: Rosati
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Lonetto
authors.forename: Niccolò
authors.initials: N
authors.lastname: Sturli
authors.forename: Doreen
authors.initials: D
authors.lastname: Kacer
authors.forename: Antonio
authors.initials: A
authors.lastname: Pennella
authors.forename: Giuseppina
authors.initials: G
authors.lastname: Ventimiglia
authors.forename: Riccardo
authors.initials: R
authors.lastname: Barucci
authors.forename: Annamaria
authors.initials: A
authors.lastname: Piscazzi
authors.forename: Igor
authors.initials: I
authors.lastname: Prudovsky
authors.forename: Matteo
authors.initials: M
authors.lastname: Landriscina
authors.forename: Niccolò
authors.initials: N
authors.lastname: Marchionni
authors.forename: Francesca
authors.initials: F
authors.lastname: Tarantini
mesh_terms: D000728:Androgens / Q000378:metabolism*; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism*; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D000860:Hypoxia; D008297:Male; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D018358:Neuroendocrine Tumors / Q000378:metabolism; D010100:Oxygen / Q000008:administration & dosage; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051881:Receptor, Notch1 / Q000235:genetics / Q000378:metabolism*; D051883:Receptor, Notch2 / Q000235:genetics / Q000378:metabolism*; D000072056:Transcription Factor HES-1
chemical_list: D000728:Androgens; D051792:Basic Helix-Loop-Helix Proteins; D018797:Cell Cycle Proteins; D018398:Homeodomain Proteins; D009419:Nerve Tissue Proteins; D010100:Oxygen; D051881:Receptor, Notch1; D051883:Receptor, Notch2; D000072056:Transcription Factor HES-1; C485631:HEY1 protein, human; C498695:NEUROG3 protein, human; C497761:NOTCH1 protein, human; C497764:NOTCH2 protein, human; C078493:HES1 protein, human