Rosanò Laura, Spinella Francesca, Genovesi Giulia, Di Castro Valeriana, Natali Pier Giorgio, Bagnato Anna
Laboratory of Molecular Pathology and Ultrastructure, Regina Elena Cancer Institute, Rome, Italy.
J Cardiovasc Pharmacol. 2004 Nov;44 Suppl 1:S136-9. doi: 10.1097/01.fjc.0000166247.35992.dd.
Expression of endothelin-B receptor gradually increases as melanocytic lesions progress to melanoma, suggesting that endothelin-B receptor and its ligands, endothelin-1 and endothelin- 3, play a role in the melanoma progression. The selective blockade of endothelin-B receptor results in inhibition of focal adhesion kinase and mitogen-activated protein kinase phosphorylation and cell proliferation induced by endothelins in human melanoma cell lines. In these cells, endothelins induce downregulation of E-cadherin expression and concomitant upregulation of transcriptional factor Snail. Activation of the endothelin-B receptor pathway by endothelins also upregulates N-cadherin, phosphorylates the gap junctional protein connexin 43, increases alphavbeta3 and alpha2beta1 integrin expression and tumor proteolytic activity, thus enhancing endothelin-B receptor-mediated cell adhesion, migration and invasiveness. In this study we demonstrated that activation of the endothelin-B receptor pathway by endothelin-1 and endothelin-3 contributes to disruption of normal host-tumor interactions by downregulating, at mRNA and protein levels, the expression of E-cadherin and associated alpha-catenin and beta-catenin adhesion proteins, which are critical for E-cadherin function. A-192621, an orally active non-peptide endothelin-B receptor antagonist, significantly inhibited melanoma growth in nude mice, suggesting that the pharmacological interruption of endothelin-B receptor signaling by endothelin-B receptor antagonist may represent a new therapeutic approach in the treatment of cutaneous melanoma.
随着黑素细胞病变进展为黑色素瘤，内皮素B受体的表达逐渐增加，这表明内皮素B受体及其配体内皮素-1和内皮素-3在黑色素瘤进展中发挥作用。选择性阻断内皮素B受体可抑制人黑色素瘤细胞系中粘着斑激酶和丝裂原活化蛋白激酶的磷酸化以及内皮素诱导的细胞增殖。在这些细胞中，内皮素可诱导E-钙黏蛋白表达下调，并伴随转录因子Snail上调。内皮素激活内皮素B受体途径还可上调N-钙黏蛋白，使缝隙连接蛋白连接蛋白43磷酸化，增加αvβ3和α2β1整合素表达以及肿瘤蛋白水解活性，从而增强内皮素B受体介导的细胞黏附、迁移和侵袭能力。在本研究中，我们证明内皮素-1和内皮素-3激活内皮素B受体途径，通过在mRNA和蛋白质水平下调对E-钙黏蛋白功能至关重要的E-钙黏蛋白及相关α-连环蛋白和β-连环蛋白黏附蛋白的表达，导致正常宿主与肿瘤相互作用的破坏。口服活性非肽类内皮素B受体拮抗剂A-192621可显著抑制裸鼠黑色素瘤生长，这表明内皮素B受体拮抗剂对内皮素B受体信号传导的药理学阻断可能代表一种治疗皮肤黑色素瘤的新方法。
