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

Abstract

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 α5 integrin (fibronectin receptor component), the antibody-mediated blockade or RNA interferencemediated knockdown of which blocked survivin-enhanced migration. Knockdown of α5 integrin did not affect Akt activation, but inhibition of Akt phosphorylation prevented α5 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 α5 integrin. Cancer Res; 70(20); 7927-37. ©2010 AACR.

Integrin α5β1 and p53 convergent pathways in the control of anti-apoptotic proteins PEA-15 and survivin in high-grade glioma

“…8,26 Previous works suggested that survivin positively regulates the α5 integrin expression. 35,36 We therefore investigated if survivin depletion may affect α5 integrin expression in glioma cells. In U87MG-α5 high cells, Nutlin-3a treatment or survivin depletion led to a decrease in α5 integrin expression level (Figure 6a), which was further significantly and dose dependently enhanced by K34c (Figure 6b).…”

Immunohistochemical expression and serum level of survivin protein in colorectal cancer patients

“…The data are, however, inconsistent with the results published in studies by Shintani et al (20) and Qi et al (21), which found that positive survivin expression was more frequent in the nucleus than in the cytoplasm of cancer cells in CRC patients. Survivin as an apoptotic protein may condition tumor aggressiveness and tumor cell invasiveness, including lymph node involvement and distant metastases (22). It has been shown that survivin may determine, via different signaling pathways, the capacity of prostate and breast cancer cells to metastasize (22,23).…”

“…Survivin as an apoptotic protein may condition tumor aggressiveness and tumor cell invasiveness, including lymph node involvement and distant metastases (22). It has been shown that survivin may determine, via different signaling pathways, the capacity of prostate and breast cancer cells to metastasize (22,23). Single studies have confirmed this potential of survivin in CRC patients.…”

Sulfatides Inhibit Adhesion, Migration, and Invasion of Murine Melanoma B16F10 Cell Line <i>in Vitro</i>

“…3) Signaling pathways promoting migration and invasion include integrin and Akt. 24) Whether the sulfatides primarily inhibited integrin expression or subsequent downward signaling pathways simultaneously was not clarified in our study, but should be investigated in the future. Further studies are needed to confirm the suppressive effects of sulfatides on adhesion, migration, and invasion of other tumor cell lines, and the effects should be confirmed in vivo studies.…”