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Endothelin Axis Is a Target of the Lung Metastasis Suppressor Gene RhoGDI2

Departments of ¹ Molecular Physiology and Biological Physics, ² Pathology, ³ Health Evaluation Sciences, Division of Biostatistics, and ⁴ Medicine, Division of Endocrinology, University of Virginia, Charlottesville, Virginia; and ⁵ Genomics Institute of the Novartis Research Foundation, San Diego, California

Requests for reprints: Dan Theodorescu, Department of Urology, University of Virginia Health Sciences Center, Box 800422, Charlottesville, VA 22908. Phone: 434-924-0042; Fax: 434-982-3652; E-mail: dt9d{at}virginia.edu.

Half of patients treated for locally advanced bladder cancer relapse with often fatal metastatic disease to the lung. We have recently shown that reduced expression of the GDP dissociation inhibitor, RhoGDI2, is associated with decreased survival of patients with advanced bladder cancer. However, the effectors by which RhoGDI2 affects metastasis are unknown. Here we use DNA microarrays to identify genes suppressed by RhoGDI2 reconstitution in lung metastatic bladder cancer cell lines. We identify such RNAs and focus only on those that also increase with tumor stage in human bladder cancer samples to discover only clinically relevant targets of RhoGDI2. Levels of endothelin-1 (ET-1), a potent vasoconstrictor, were affected by both RhoGDI2 reconstitution and tumor stage. To test the hypothesis that the endothelin axis is important in lung metastasis, lung metastatic bladder carcinoma cells were injected in mice treated with the endothelin receptor–specific antagonist, atrasentan, thereby blocking engagement of the up-regulated ET-1 ligand with its cognate receptor. Endothelin antagonism resulted in a dramatic reduction of lung metastases, similar to the effect of reexpressing RhoGDI2 in these metastatic cells. Taken together, these experiments show a novel approach of identifying therapeutic targets downstream of metastasis suppressor genes. The data also suggest that blockade of the ET-1 axis may prevent lung metastasis, a new therapeutic concept that warrants clinical evaluation.

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