Survivin Enhances Motility of Melanoma Cells by Supporting Akt Activation and α5 Integrin Upregulation

Survivin expression in melanoma is inversely correlated with patient survival. Transgenic mice harboring melanocyte-specific overexpression of survivin exhibit increased susceptibility to UV-induced melanoma and metastatic progression. To understand the mechanistic basis for metastatic progression, we investigated the effects of survivin on the motility of human melanocytes and melanoma cells. We found that survivin overexpression enhanced migration on fibronectin and invasion through Matrigel, whereas survivin knockdown under subapoptotic conditions blocked migration and invasion. In melanocytes, survivin overexpression activated the Akt and mitogen-activated protein kinase pathways. Akt phosphorylation was required for survivin-enhanced migration and invasion, whereas Erk phosphorylation was required only for enhanced invasion. In both melanocytes and melanoma cells, survivin overexpression was associated with upregulation of alpha 5 integrin (fibronectin receptor component), the antibody-mediated blockade or RNA interference-mediated knockdown of which blocked survivin-enhanced migration. Knockdown of a5 integrin did not affect Akt activation, but inhibition of Akt phosphorylation prevented a5 integrin upregulation elicited by survivin overexpression. Together, our results showed that survivin enhanced the migration and invasion of melanocytic cells and suggested that survivin may promote melanoma metastasis by supporting Akt-dependent upregulation of a5 integrin. Cancer Res; 70(20); 7927-37. (C) 2010 AACR.