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Endothelin axis is a target of the lung metastasis suppressor gene RhoGDI2
Brian Titus1, Henry F Frierson, Mark Conaway
1Department of Molecular Physiology and Biological Physics, University of Virginia, Charlottesville, Virginia 22908, USA.
Abstract:
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.
Insights
Reduced RhoGDI2 expression in bladder cancer promotes lung metastasis. Blocking endothelin-1 signaling significantly reduced metastasis, suggesting a new therapeutic strategy for advanced bladder cancer patients.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Metastasis Research
Background:
- Locally advanced bladder cancer frequently metastasizes to the lung, leading to poor patient survival.
- Reduced expression of Rho GDP dissociation inhibitor 2 (RhoGDI2) correlates with decreased survival in advanced bladder cancer.
- The specific molecular mechanisms by which RhoGDI2 influences metastasis remain largely unknown.
Purpose of the Study:
- To identify downstream effectors of the metastasis suppressor RhoGDI2 in bladder cancer.
- To investigate the role of the endothelin axis in bladder cancer lung metastasis.
- To evaluate endothelin receptor antagonism as a potential therapeutic strategy.
Main Methods:
- DNA microarrays were used to identify genes suppressed by RhoGDI2 reconstitution in metastatic bladder cancer cell lines.
- Gene expression analysis was correlated with tumor stage in human bladder cancer samples.
- In vivo studies involved injecting metastatic bladder cancer cells into mice treated with the endothelin receptor antagonist, atrasentan.
Main Results:
- Endothelin-1 (ET-1) levels were found to be modulated by both RhoGDI2 expression and tumor stage.
- Pharmacological blockade of the endothelin receptor significantly reduced lung metastases in a mouse model.
- The observed reduction in lung metastases mirrored the effect of RhoGDI2 reexpression.
Conclusions:
- This study identifies a novel approach for discovering therapeutic targets downstream of metastasis suppressor genes.
- The endothelin axis is implicated as a critical pathway in bladder cancer lung metastasis.
- Targeting the endothelin-1 pathway presents a promising, clinically relevant therapeutic concept for preventing metastasis in advanced bladder cancer.
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