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 ETA 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.