title: Role of endothelin axis in progression to aggressive phenotype of prostate adenocarcinoma.
abstract: BACKGROUND
  Mitogenic and anti-apoptotic actions of endothelin-1 (ET-1) are mediated through endothelin A (ET(A)) receptors. We investigated endothelin receptor expression in increasingly aggressive phenotype and in vivo effects of combination therapy using ET(A) antagonist with paclitaxel.
  
  
  METHODS
  Dunning prostate cancer cells ranged in aggressiveness from non-tumorigenic G, to tumorigenic, non-metastatic AT-1, and to tumorigenic and metastatic MLL. Binding assays were performed alongside Q-PCR to assess receptor density. MLL xenografts were treated with vehicle, atrasentan, paclitaxel, and paclitaxel+atrasentan.
  
  
  RESULTS
  Saturation binding assays demonstrated endothelin receptor density of MLL and AT-1 cells seven- and threefold higher than G cells, respectively. Q-PCR showed 9- and 4.5-fold greater ET(A) mRNA expression in MLL and AT-1 than G cells, respectively and no endothelin receptor B (ET(B)) expression. Combination therapy had significant effect on reduction of tumor volume than paclitaxel or atrasentan alone.
  
  
  CONCLUSIONS
  ET(A) expression increases in aggressive prostate carcinoma. ET(A) blockade combined with paclitaxel may reduce tumor growth in advanced prostate carcinoma.
authors.affiliation: Department of Urology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
authors.forename: Geeta
authors.initials: G
authors.lastname: Godara
authors.forename: Grant W
authors.initials: GW
authors.lastname: Cannon
authors.forename: Glenn M
authors.initials: GM
authors.lastname: Cannon
authors.forename: Robert R
authors.initials: RR
authors.lastname: Bies
authors.forename: Joel B
authors.initials: JB
authors.lastname: Nelson
authors.forename: Beth R
authors.initials: BR
authors.lastname: Pflug
mesh_terms: D000230:Adenocarcinoma / Q000473:pathology*; D000818:Animals; D018450:Disease Progression; D065130:Endothelin A Receptor Antagonists; D019332:Endothelin-1 / Q000502:physiology*; D006801:Humans; D008297:Male; D051379:Mice; D010641:Phenotype; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000473:pathology*; D044022:Receptor, Endothelin A / Q000032:analysis; D044023:Receptor, Endothelin B / Q000032:analysis
chemical_list: D065130:Endothelin A Receptor Antagonists; D019332:Endothelin-1; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B