Bibliographic Details
| Title: |
The sodium pump α1 sub-unit: a disease progression–related target for metastatic melanoma treatment. |
| Authors: |
Mathieu, Véronique, Pirker, Christine, de Lassalle, Elisabeth Martin, Vernier, Mathieu, Mijatovic, Tatjana, DeNeve, Nancy, Gaussin, Jean-François, Dehoux, Mischael, Lefranc, Florence, Berger, Walter, Kiss, Robert |
| Source: |
Journal of Cellular & Molecular Medicine; Sep2009, Vol. 13 Issue 9b, p3960-3972, 13p, 1 Color Photograph, 1 Black and White Photograph, 2 Charts, 4 Graphs |
| Subject Terms: |
SODIUM/POTASSIUM ATPase, MELANOMA, TUMORS, CARDENOLIDES, APOPTOSIS |
| Abstract: |
Melanomas remain associated with dismal prognosis because they are naturally resistant to apoptosis and they markedly metastasize. Up-regulated expression of sodium pump α sub-units has previously been demonstrated when comparing metastatic to non-metastatic melanomas. Our previous data revealed that impairing sodium pump α1 activity by means of selective ligands, that are cardiotonic steroids, markedly impairs cell migration and kills apoptosis-resistant cancer cells. The objective of this study was to determine the expression levels of sodium pump α sub-units in melanoma clinical samples and cell lines and also to characterize the role of α1 sub-units in melanoma cell biology. Quantitative RT-PCR, Western blotting and immunohistochemistry were used to determine the expression levels of sodium pump α sub-units. In vitro cytotoxicity of various cardenolides and of an anti-α1 siRNA was evaluated by means of MTT assay, quantitative videomicroscopy and through apoptosis assays. The in vivo activity of a novel cardenolide UNBS1450 was evaluated in a melanoma brain metastasis model. Our data show that all investigated human melanoma cell lines expressed high levels of the α1 sub-unit, and 33% of human melanomas displayed significant α1 sub-unit expression in correlation with the Breslow index. Furthermore, cardenolides (notably UNBS1450; currently in Phase I clinical trials) displayed marked anti-tumour effects against melanomas in vitro. This activity was closely paralleled by decreases in cMyc expression and by increases in apoptotic features. UNBS1450 also displayed marked anti-tumour activity in the aggressive human metastatic brain melanoma model in vivo. The α1 sodium pump sub-unit could represent a potential novel target for combating melanoma. [ABSTRACT FROM AUTHOR] |
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| Database: |
Complementary Index |
