title: Survivin enhances motility of melanoma cells by supporting Akt activation and {alpha}5 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 interference-mediated 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.
authors.affiliation: Departments of Dermatology and Oncological Sciences, and the Huntsman Cancer Institute; University of Utah Health Sciences Center, Salt Lake City, UT 84112, USA.
authors.forename: Jodi A
authors.initials: JA
authors.lastname: McKenzie
authors.forename: Tong
authors.initials: T
authors.lastname: Liu
authors.forename: Agnessa G
authors.initials: AG
authors.lastname: Goodson
authors.forename: Douglas
authors.initials: D
authors.lastname: Grossman
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology*; D004789:Enzyme Activation; D052816:Foreskin / Q000166:cytology; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins; D039081:Integrin alpha5beta1 / Q000235:genetics*; D008297:Male; D008544:Melanocytes / Q000166:cytology / Q000502:physiology; D008545:Melanoma / Q000473:pathology / Q000503:physiopathology*; D008869:Microtubule-Associated Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009361:Neoplasm Invasiveness; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics* / Q000378:metabolism; D034622:RNA Interference / Q000502:physiology; D000077022:Survivin; D015854:Up-Regulation
chemical_list: C107489:BIRC5 protein, human; D051034:Inhibitor of Apoptosis Proteins; D039081:Integrin alpha5beta1; D008869:Microtubule-Associated Proteins; D000077022:Survivin; D051057:Proto-Oncogene Proteins c-akt; D020928:Mitogen-Activated Protein Kinases
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