title: Osteoblasts can stimulate prostate cancer growth and transcriptionally down-regulate PSA expression in cell line models.
abstract: BACKGROUND
  To investigate the effect of bone environment on cellular proliferation, mature prostate-specific antigen (PSA) production and secretion, and PSA transcriptional regulation of prostate cancer cells.
  
  
  METHODS
  Androgen-independent C4-2 prostate cancer cells were co-cultured with various osteoblastic cells in a transwell system. Proliferation was measured via cell counting and MTT assay. Lactate and PSA were determined in the conditioned media (CM). Transcriptional activity of the full-length PSA promoter (6.1 kilobases) and of 3 deletion constructs was determined via luciferase reporter assay upon exposure to CM from various osteoblastic cell lines.
  
  
  RESULTS
  Osteoblastic bone cells and CM, but not control cells (fibroblast) or CM, reproducibly stimulated the proliferation of C4-2 cells. The co-culture system, PSA production by C4-2 cells transiently decreased when in co-culture with osteoblastic, but not with control cells. After abundant prostate cell proliferation, the secreted PSA levels rose exponentially. Addition of CM from osteoblastic cells, but not control cells, consistently decreased (about 3-fold) the transcriptional activity of the PSA promoter in C4-2 cells. Deletion construct analysis of the PSA promoter revealed that the transcriptional down-regulation is dually controlled by elements close to the TATA and upstream androgen responsive (ARE(III)) components.
  
  
  CONCLUSIONS
  The osteoblastic environment stimulates prostate cancer cell proliferation but reduces PSA production initially. The mechanism of PSA down-regulation is transcriptional, most likely in response to soluble factors present in the osteoblastic bone stromal cell CM. Transcriptional down-regulation appears to be mediated by elements near both the TATA box and the ARE(III) component.
authors.affiliation: Department of Urology, University of Minnesota, Minneapolis, MN 55455, USA.
authors.forename: Yingming
authors.initials: Y
authors.lastname: Li
authors.forename: Robert A
authors.initials: RA
authors.lastname: Sikes
authors.forename: Bahaa S
authors.initials: BS
authors.lastname: Malaeb
authors.forename: Fan
authors.initials: F
authors.lastname: Yeung
authors.forename: Andrew
authors.initials: A
authors.lastname: Law
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Graham
authors.forename: Min
authors.initials: M
authors.lastname: Pei
authors.forename: Chinghai
authors.initials: C
authors.lastname: Kao
authors.forename: Joel
authors.initials: J
authors.lastname: Nelson
authors.forename: Kenneth S
authors.initials: KS
authors.lastname: Koeneman
authors.forename: Leland W K
authors.initials: LW
authors.lastname: Chung
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D018920:Coculture Techniques; D017077:Culture Media, Conditioned / Q000378:metabolism / Q000494:pharmacology; D015536:Down-Regulation; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology*; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D010006:Osteoblasts / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000235:genetics; D017430:Prostate-Specific Antigen / Q000096:biosynthesis* / Q000235:genetics; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic
chemical_list: D017077:Culture Media, Conditioned; D017430:Prostate-Specific Antigen