Role of endothelin axis in progression to aggressive phenotype of prostate adenocarcinoma.
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.
Godara
Geeta
G
Department of Urology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
Cannon
Grant W
GW
Cannon
Glenn M
GM
Bies
Robert R
RR
Nelson
Joel B
JB
Pflug
Beth R
BR
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
D065130:Endothelin A Receptor Antagonists; D019332:Endothelin-1; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B