Open AccessThe sodium pump α1 sub‐unit: a disease progression–related target for metastatic melanoma treatment
Author(s) -
Mathieu Véronique,
Pirker Christine,
Martin de Lassalle Elisabeth,
Vernier Mathieu,
Mijatovic Tatjana,
DeNeve Nancy,
Gaussin JeanFrançois,
Dehoux Mischael,
Lefranc Florence,
Berger Walter,
Kiss Robert
Publication year - 2009
Publication title -
journal of cellular and molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.44
H-Index - 130
eISSN - 1582-4934
pISSN - 1582-1838
DOI - 10.1111/j.1582-4934.2009.00708.x
Subject(s) - melanoma , in vivo , apoptosis , cancer research , in vitro , immunohistochemistry , cell culture , cytotoxicity , cell , mtt assay , metastasis , chemistry , biology , cancer , pathology , immunology , medicine , biochemistry , genetics , microbiology and biotechnology
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.