title: Impact of hypoxia on the metastatic potential of human prostate cancer cells.
abstract: OBJECTIVE
  Intratumoral hypoxia is known to be associated with radioresistance and metastasis. The present study examined the effect of acute and chronic hypoxia on the metastatic potential of prostate cancer PC-3, DU145, and LNCaP cells.
  
  
  METHODS
  Cell proliferation and clonogenicity were tested by MTT assay and colony formation assay, respectively. "Wound-healing" and Matrigel-based chamber assays were used to monitor cell motility and invasion. Hypoxia-inducible factor 1 alpha (HIF-1α) expression was tested by Western blot, and HIF-1-target gene expression was detected by real-time polymerase chain reaction. Secretion of matrix metalloproteinases (MMPs) was determined by gelatin zymography.
  
  
  RESULTS
  When PC-3 cells were exposed to 1% oxygen (hypoxia) for various periods of time, chronic hypoxia (≥24 h) decreased cell proliferation and induced cell death. In contrast, prostate cancer cells exposed to acute hypoxia (≤6 h) displayed increased motility, clonogenic survival, and invasive capacity. At the molecular level, both hypoxia and anoxia transiently stabilized HIF-1α. Exposure to hypoxia also induced the early expression of MMP-2, an invasiveness-related gene. Treatment with the HIF-1 inhibitor YC-1 attenuated the acute hypoxia-induced migration, invasion, and MMP-2 activity.
  
  
  CONCLUSIONS
  The length of oxygen deprivation strongly affected the functional behavior of all three prostate cancer cell lines. Acute hypoxia in particular was found to promote a more aggressive metastatic phenotype.
authors.affiliation: Department of Radiation Oncology, University of Florida Shands Cancer Center, Gainesville, FL 32610, USA. daiyao@ufl.edu
authors.forename: Yao
authors.initials: Y
authors.lastname: Dai
authors.forename: Kyungmi
authors.initials: K
authors.lastname: Bae
authors.forename: Dietmar W
authors.initials: DW
authors.lastname: Siemann
mesh_terms: D016923:Cell Death / Q000502:physiology; D015687:Cell Hypoxia / Q000502:physiology*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation; D002470:Cell Survival / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D051793:Hypoxia-Inducible Factor 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D007191:Indazoles / Q000494:pharmacology; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000235:genetics / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism; D061965:Matrix Metalloproteinase Inhibitors; D009361:Neoplasm Invasiveness / Q000235:genetics / Q000503:physiopathology / Q000517:prevention & control; D009363:Neoplasm Proteins / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D013997:Time Factors; D014410:Tumor Stem Cell Assay
chemical_list: D004791:Enzyme Inhibitors; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007191:Indazoles; D061965:Matrix Metalloproteinase Inhibitors; D009363:Neoplasm Proteins; C090937:3-(5'-hydroxymethyl-2'-furyl)-1-benzylindazole; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9