The sodium pump alpha1 sub-unit: a disease progression-related target for metastatic melanoma treatment.
Melanomas remain associated with dismal prognosis because they are naturally resistant to apoptosis and they markedly metastasize. Up-regulated expression of sodium pump alpha sub-units has previously been demonstrated when comparing metastatic to non-metastatic melanomas. Our previous data revealed that impairing sodium pump alpha1 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 alpha sub-units in melanoma clinical samples and cell lines and also to characterize the role of alpha1 sub-units in melanoma cell biology. Quantitative RT-PCR, Western blotting and immunohistochemistry were used to determine the expression levels of sodium pump alpha sub-units. In vitro cytotoxicity of various cardenolides and of an anti-alpha1 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 alpha1 sub-unit, and 33% of human melanomas displayed significant alpha1 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 alpha1 sodium pump sub-unit could represent a potential novel target for combating melanoma.
Mathieu
Véronique
V
Laboratory of Toxicology, Institute of Pharmacy, Free University of Brussels, ULB, Brussels, Belgium.
Pirker
Christine
C
Martin de Lassalle
Elisabeth
E
Vernier
Mathieu
M
Mijatovic
Tatjana
T
DeNeve
Nancy
N
Gaussin
Jean-François
JF
Dehoux
Mischael
M
Lefranc
Florence
F
Berger
Walter
W
Kiss
Robert
R
D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology; D017209:Apoptosis; D002298:Cardenolides / Q000494:pharmacology; D045744:Cell Line, Tumor; D003606:Dacarbazine / Q000031:analogs & derivatives / Q000494:pharmacology; D018450:Disease Progression; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008545:Melanoma / Q000378:metabolism* / Q000628:therapy*; D051379:Mice; D008819:Mice, Nude; D018715:Microscopy, Video / Q000379:methods; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation; D000254:Sodium-Potassium-Exchanging ATPase / Q000378:metabolism*; D000077204:Temozolomide
D018906:Antineoplastic Agents, Alkylating; D002298:Cardenolides; C510008:UNBS 1450; D003606:Dacarbazine; D000254:Sodium-Potassium-Exchanging ATPase; D000077204:Temozolomide