Ran signaling in melanoma: Implications for the development of alternative therapeutic strategies

Emilia Caputo, Ena Wang, Anna Valentino, Stefania Crispi, Valeria De Giorgi, Annalisa Fico, Bartolomea Ficili, Mariaelena Capone, Anna Maria Anniciello, Ernesta Cavalcanti, Gerardo Botti, Nicola Mozzillo, Paolo A. Ascierto, Francesco M. Marincola, Salvatore Travali

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Abstract

We performed a comparative study between two human metastatic melanoma cell lines (A375 and 526), and melanocytes (FOM78) by gene expression profiling and pathway analysis, using Gene Set Enrichment Analysis (GSEA) and Ingenuity Pathway Analysis (IPA) software. Genes involved in Ran signaling were significantly over-represented (p ≤ 0.001) and up-regulated in melanoma cells. A melanoma-associated molecular pathway was identified, where Ran, Aurora Kinase A (AurkA) and TERT were up-regulated, while c-myc and PTEN were down-regulated. A consistent high Ran and AurkA gene expression was detected in about 48% and 53%, respectively, of 113 tissue samples from metastatic melanoma patients. AurkA down-regulation was observed in melanoma cells, by Ran knockdown, suggesting AurkA protein is a Ran downstream target. Furthermore, AurkA inhibition, by exposure of melanoma cells to MLN8054, a specific AurKA inhibitor, induced apoptosis in both melanoma cell lines and molecular alterations in the IPA-identified molecular pathway. These alterations differed between cell lines, with an up-regulation of c-myc protein level observed in 526 cells and a slight reduction seen in A375 cells. Moreover, Ran silencing did not affect the A375 invasive capability, while it was enhanced in 526 cells, suggesting that Ran knockdown, by AurkA down-regulation, resulted in a Ran-independent enhanced melanoma cell invasion. Finally, AurK A inhibition induced a PTEN up-regulation and its action was independent of B-RAF mutational status. These findings provide insights relevant for the development of novel therapeutic strategies as well as for a better understanding of mechanisms underlying therapy resistance in melanoma.

Original languageEnglish
Pages (from-to)286-296
Number of pages11
JournalCancer Letters
Volume357
Issue number1
DOIs
Publication statusPublished - 1 Feb 2015

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Keywords

  • Aurora kinase A in melanoma
  • Gene expression
  • Pathway analysis
  • Ran signaling
  • Targeted therapy

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Caputo, E., Wang, E., Valentino, A., Crispi, S., De Giorgi, V., Fico, A., Ficili, B., Capone, M., Anniciello, A. M., Cavalcanti, E., Botti, G., Mozzillo, N., Ascierto, P. A., Marincola, F. M., & Travali, S. (2015). Ran signaling in melanoma: Implications for the development of alternative therapeutic strategies. Cancer Letters, 357(1), 286-296. https://doi.org/10.1016/j.canlet.2014.11.033