RSK1 activation promotes invasion in nodular melanoma.

Abstract

The two major melanoma histologic subtypes, superficial spreading and nodular melanomas, differ in their speed of dermal invasion but converge biologically once they invade and metastasize. Herein, we tested the hypothesis that distinct molecular alterations arising in primary melanoma cells might persist as these tumors progress to invasion and metastasis. Ribosomal protein S6 kinase, 90 kDa, polypeptide 1 (RSK1; official name RPS6KA1) was significantly hyperactivated in human melanoma lines and metastatic tissues derived from nodular compared with superficial spreading melanoma. RSK1 was constitutively phosphorylated at Ser-380 in nodular but not superficial spreading melanoma and did not directly correlate with BRAF or MEK activation. Nodular melanoma cells were more sensitive to RSK1 inhibition using siRNA and the pharmacological inhibitor BI-D1870 compared with superficial spreading cells. Gene expression microarray analyses revealed that RSK1 orchestrated a program of gene expression that promoted cell motility and invasion. Differential overexpression of the prometastatic matrix metalloproteinase 8 and tissue inhibitor of metalloproteinases 1 in metastatic nodular compared with metastatic superficial spreading melanoma was observed. Finally, using an in vivo zebrafish model, constitutive RSK1 activation increased melanoma invasion. Together, these data reveal a novel role for activated RSK1 in the progression of nodular melanoma and suggest that melanoma originating from different histologic subtypes may be biologically distinct and that these differences are maintained as the tumors invade and metastasize.

• Authors: Amel Salhi, Joshua A Farhadian, Keith M Giles, Eleazar Vega-Saenz de Miera, Ines P Silva, Caitlin Bourque, Karen Yeh, Sagar Chhangawala, Jinhua Wang, Fei Ye, David Y Zhang, Eva Hernando-Monge, Yariv Houvras, Iman Osman
• Journal: The American journal of pathology (Am J Pathol) Vol. 185 Issue 3 Pg. 704-16 (Mar 2015) ISSN: 1525-2191 [Electronic] United States
• PMID: 25579842 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

Chemical References

• RPS6KA1 protein, human
• Ribosomal Protein S6 Kinases, 90-kDa

Topics

• Animals
• Cell Line, Tumor
• Cell Movement
• Disease Progression
• Humans
• Melanoma (metabolism, pathology)
• Neoplasm Invasiveness (pathology)
• Phosphorylation
• Ribosomal Protein S6 Kinases, 90-kDa (metabolism)
• Skin Neoplasms (metabolism, pathology)
• Zebrafish