The sodium pump α1 sub-unit: a disease progression–related target for metastatic melanoma treatment
Véronique Mathieu
Laboratory of Toxicology, Institute of Pharmacy, Free University of Brussels (ULB), Brussels, Belgium
Search for more papers by this authorChristine Pirker
Department of Medicine I, Institute of Cancer Research, Medical University of Vienna, Vienna, Austria
Search for more papers by this authorElisabeth Martin de Lassalle
Pôle de Pathologie, CHRU Lille, France
Search for more papers by this authorFlorence Lefranc
Laboratory of Toxicology, Institute of Pharmacy, Free University of Brussels (ULB), Brussels, Belgium
Department of Neurosurgery, Erasme University Hospital, Brussels, Belgium
Search for more papers by this authorWalter Berger
Department of Medicine I, Institute of Cancer Research, Medical University of Vienna, Vienna, Austria
Search for more papers by this authorCorresponding Author
Robert Kiss
Laboratory of Toxicology, Institute of Pharmacy, Free University of Brussels (ULB), Brussels, Belgium
Correspondence to: Robert KISS, Ph.D., Laboratory of Toxicology, Institute of Pharmacy, Free University of Brussels (ULB), Campus de la Plaine, Boulevard du Triomphe 1050, Brussels, Belgium.Tel.: +32-477-6220-83Fax: +32 2 332 53 35E-mail: [email protected]Search for more papers by this authorVéronique Mathieu
Laboratory of Toxicology, Institute of Pharmacy, Free University of Brussels (ULB), Brussels, Belgium
Search for more papers by this authorChristine Pirker
Department of Medicine I, Institute of Cancer Research, Medical University of Vienna, Vienna, Austria
Search for more papers by this authorElisabeth Martin de Lassalle
Pôle de Pathologie, CHRU Lille, France
Search for more papers by this authorFlorence Lefranc
Laboratory of Toxicology, Institute of Pharmacy, Free University of Brussels (ULB), Brussels, Belgium
Department of Neurosurgery, Erasme University Hospital, Brussels, Belgium
Search for more papers by this authorWalter Berger
Department of Medicine I, Institute of Cancer Research, Medical University of Vienna, Vienna, Austria
Search for more papers by this authorCorresponding Author
Robert Kiss
Laboratory of Toxicology, Institute of Pharmacy, Free University of Brussels (ULB), Brussels, Belgium
Correspondence to: Robert KISS, Ph.D., Laboratory of Toxicology, Institute of Pharmacy, Free University of Brussels (ULB), Campus de la Plaine, Boulevard du Triomphe 1050, Brussels, Belgium.Tel.: +32-477-6220-83Fax: +32 2 332 53 35E-mail: [email protected]Search for more papers by this authorAbstract
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.
References
- 1 Jemal A, Siegel R, Ward E, et al . Cancer statistics, 2008. CA Cancer J Clin. 2008; 58: 71–96.
- 2 Onken MD, Worley LA, Ehlers JP, et al . Gene expression profiling in uveal melanoma reveals two molecular classes and predicts metastatic death. Cancer Res. 2004; 64: 7205–9.
- 3 Lefranc F, Facchini V, Kiss R. Proautophagic drugs: a novel means to combat apoptosis-resistant cancers, with a special emphasis on glioblastomas. Oncologist. 2007; 12: 1395–403.
- 4 Jaeger J, Koczan D, Thiesen HJ, et al . Gene expression signatures for tumor progression, tumor subtype, and tumor thickness in laser-microdissected melanoma tissues. Clin Cancer Res. 2007; 13: 806–15.
- 5 Pastorino F, Brignole C, Marimpietri D, et al . Targeted liposomal c-myc antisense oligodeoxynucleotides induce apoptosis and inhibit tumor growth and metastases in human melanoma models. Clin Cancer Res. 2003; 9: 4595–605.
- 6 Lejeune FJ, Rimoldi D, Speiser D. New approaches in metastatic melanoma: biological and molecular targeted therapies. Expert Rev Anticancer Ther. 2007; 7: 701–13.
- 7 Mathieu V, Le Mercier M, De Neve N, et al . Galectin-1 knockdown increases sensitivity to temozolomide in a B16F10 mouse metastatic melanoma model. J Invest Dermatol. 2007; 127: 2399–410.
- 8 Tawbi HA, Kirkwood JM. Management of metastatic melanoma. Semin Oncol. 2007; 34: 532–45.
- 9 Mijatovic T, Van Quaquebeke E, Delest B, et al . Cardiotonic steroids on the road to anti-cancer therapy. BBA Rev Cancer. 2007; 1776: 32–57.
- 10 Lefranc F, Mijatovic T, Kondo Y, et al . Targeting the alpha1 subunit of the sodium pump to combat glioblastoma cells. Neurosurgery. 2008; 62: 211–21.
- 11 Lefranc F, Kiss R. The sodium pump alpha1 subunit as a potential target to combat apoptosis-resistant glioblastomas. Neoplasia. 2008; 10: 198–206.
- 12 Boukerche H, Su ZZ, Kang DC, et al . Identification and cloning of genes displaying elevated expression as a consequence of metastatic progression in human melanoma cells by rapid subtraction hybridization. Gene. 2004; 343: 191–201.
- 13 Mijatovic T, Roland I, Van Quaquebeke E, et al . The alpha-1 subunit of the sodium pump could represent a novel target to combat non-small cell lung cancers. J Pathol. 2007; 212: 170–9.
- 14 Seligson DB, Rajasekaran SA, Yu H, et al . Na,K-adenosine triphosphatase alpha1-subunit predicts survival of renal clear cell carcinoma. J Urol. 2008; 179: 338–45.
- 15 Sakai H, Suzuki T, Maeda M, et al . Up-regulation of Na(+),K(+)-ATPase alpha-3 isoform and down-regulation of the alpha-1 isoform in human colorectal cancer. FEBS Lett. 2004; 563: 151–4.
- 16 Mijatovic T, Mathieu V, Gaussin JF, et al . Cardenolide-induced lysosomal membrane permeabilization demonstrates therapeutic benefits in experimental human non-small cell lung cancers. Neoplasia. 2006; 8: 402–12.
- 17 La Porta CA. Drug resistance in melanoma: new perspectives. Curr Med Chem. 2007; 14: 387–91.
- 18 Hersey P, Zhuang L, Zhang XD. Current strategies in overcoming resistance of cancer cells to apoptosis: melanoma as a model. Int Rev Cytol. 2006; 251: 131–58.
- 19 Lefranc F, Brotchi J, Kiss R. Possible future issues in the treatment of glioblastomas: special emphasis on cell migration and the resistance of migrating glioblastoma cells to apoptosis. J Clin Oncol. 2005; 23: 2411–22.
- 20 Bucci B, D’Agnano I, Amendola D, et al . Myc down-regulation sensitizes melanoma cells to radiotherapy by inhibiting MLH1 and MSH2 mismatch repair proteins. Clin Cancer Res. 2005; 11: 2756–67.
- 21 Grover R, Chana J, Grobbelaar AO, et al . Measurement of c-myc oncogene expression provides an accurate prognostic marker for acral lentiginous melanoma. Br J Plast Surg. 1999; 52: 122–6.
- 22 Ramsden AJ, Grover R, Chana J, et al . A prospective analysis of c-myc oncoprotein levels as a prognostic marker in malignant melanoma. J Plast Reconstr Aesthet Surg. 2007; 60: 626–30.
- 23 Tulley PN, Neale M, Jackson D, et al . The relation between c-myc expression and interferon sensitivity in uveal melanoma. Br J Ophthalmol. 2004; 88: 1563–7.
- 24 Zupi G, Scarsella M, Semple SC, et al . Antitumor efficacy of bcl-2 and c-myc antisense oligonucleotides in combination with cisplatin in human melanoma xenografts: relevance of the administration sequence. Clin Cancer Res. 2005; 11: 1990–8.
- 25 Schlagbauer-Wadl H, Griffioen M, van Elsas A, et al . Influence of increased c-Myc expression on the growth characteristics of human melanoma. J Invest Dermatol. 1999; 112: 332–6.
- 26 Biroccio A, Amodei S, Antonelli A, et al . Inhibition of c-Myc oncoprotein limits the growth of human melanoma cells by inducing cellular crisis. J Biol Chem. 2003; 278: 35693–701.
- 27 Mathieu V, Mijatovic T, van Damme M, et al . Gastrin exerts pleiotropic effects on human melanoma cell biology. Neoplasia. 2005; 10: 930–43.
- 28
Berger W,
Hauptmann E,
Elbling L,
et al
.
Possible role of the multidrug resistance-associated protein (MRP) in chemoresistance of human melanoma cells.
Int J Cancer.
1997; 71: 108–15.
10.1002/(SICI)1097-0215(19970328)71:1<108::AID-IJC18>3.0.CO;2-E CAS PubMed Web of Science® Google Scholar
- 29 Van Quaquebeke E, Simon G, André A, et al . Identification of a novel cardenolide (2″-oxovoruscharin) from Calotropis procera and the hemisynthesis of novel derivatives displaying potent in vitro antitumor activities and high in vivo tolerance: structure-activity relationship analyses. J Med Chem. 2005; 48: 849–56.
- 30 Branle F, Lefranc F, Camby I, et al . Evaluation of the efficiency of chemotherapy in in vivo orthotopic models of human glioma cells with and without 1p19q deletions and in C6 rat orthotopic allografts serving for the evaluation of surgery combined with chemotherapy. Cancer. 2002; 95: 641–55.
- 31 Lefranc F, Mijatovic T, Mathieu V, et al . Characterization of gastrin-induced proangiogenic effects in vivo in orthotopic U373 experimental human glioblastomas and in vitro in human umbilical vein endothelial cells. Clin Cancer Res. 2004; 10: 8250–65.
- 32 Mijatovic T, De Nëve N, Gailly P, et al . The nucleolus and c-Myc: potential targets of cardenolide-mediated anti-tumor activity. Mol Cancer Ther. 2008; 7: 1285–96.
- 33 Dumont P, Ingrassia L, Rouzeau S, et al . The Amaryllidaceae isocarbostyril narciclasine induces apoptosis by activation of the death receptor and/or mitochondrial pathways in cancer cells but not in normal fibroblasts. Neoplasia. 2007; 9: 766–76.
- 34 Liu LY, Hu CL, Ma LJ, et al . ET-1 inhibits B-16 murine melanoma cell migration by decreasing K(+) currents. Cell Motil Cytoskeleton. 2004; 58: 127–36.
- 35 McFerrin MB, Sontheimer H. A role for ion channels in glioma cell invasion. Neuron Glia Biol. 2006; 2: 39–49.
- 36 Schwab A, Reinhardt J, Schneider SW, et al . K(+) channel-dependent migration of fibroblasts and human melanoma cells. Cell Physiol Biochem. 1999; 9: 126–32.
- 37 Molitoris BA, Geerdes A, McIntosh JR. Dissociation and redistribution of Na+,K(+)-ATPase from its surface membrane actin cytoskeletal complex during cellular ATP depletion. J Clin Invest. 1991; 88: 462–9.
- 38 Barwe SP, Anilkumar G, Moon SY, et al . Novel role for Na,K-ATPase in phosphatidylinositol 3-kinase signaling and suppression of cell motility. Mol Biol Cell. 2005; 16: 1082–94.
- 39 Cappellen D, Schlange T, Bauer M, et al . Novel c-Myc target genes mediate differential effects on cell proliferation and migration. EMBO Rep. 2007; 8: 70–6.
- 40 Larriba MJ, Valle N, Pálmer HG, et al . The inhibition of Wnt/beta-catenin signaling by 1alpha, 25-dihydroxyvitamin D3 is abrogated by Snail1 in human colon cancer cells. Endocr Relat Cancer. 2007; 14: 141–51.
- 41 Espineda CE, Chang JH, Twiss J, et al . Repression of Na,K-ATPase beta1-subunit by the transcription factor Snail in carcinoma. Mol Biol Cell. 2004; 15: 1364–73.
- 42 Imamichi Y, Menke A. Signaling pathways involved in collagen-induced disruption of the E-cadherin complex during epithelial-mesenchymal transition. Cells Tissues Organs. 2007; 185: 180–90.
- 43 Robert G, Gaggioli C, Bailet O, et al . SPARC represses E-cadherin and induces mesenchymal transition during melanoma development. Cancer Res. 2006; 66: 7516–23.
- 44 Onken MD, Ehlers JP, Worley LA, et al . Functional gene expression analysis uncovers phenotypic switch in aggressive uveal melanomas. Cancer Res. 2006; 66: 4602–9.
- 45 Sampson VB, Rong NH, Han J, et al . MicroRNA Let-7a down-regulates Myc and reverts Myc-induced growth in Burkitt Lymphoma cells. Cancer Res. 2007; 67: 9762–70.
- 46 Esquela-Kerscher A, Slack FJ. Oncomirs – microRNAs with a role in cancer. Nat Rev Cancer. 2006; 6: 259–69.
- 47 Mendell JT. MicroRNAs. Critical regulators of development, cellular physiology and malignancy. Cell Cycle. 2005; 4: 1179–84.
- 48 Gaur A, Jewell DA, Liang Y, et al . Characterization of microRNA expression levels and their biological correlates in human cancer cell lines. Cancer Res. 2007; 67: 2456–68.
- 49 Zhang L, Huang J, Yang N, et al . MicroRNAs exhibit high frequency genomic alterations in human cancer. Proc Natl Acad Sci USA. 2006; 103: 9136–41.
- 50 Cummins JM, He Y, Leary RJ, et al . The colorectal microRNAome. Proc Natl Acad Sci USA. 2006; 103: 3687–92.
Citing Literature
