GSK3[beta] Inhibition Blocks Melanoma Cell/Host Interactions by Downregulating N-Cadherin Expression and Decreasing FAK Phosphorylation

• Published in: Journal of investigative dermatology Vol. 132; no. 12; p. 2818
• Main Authors: John, Jobin K, Paraiso, Kim H T, Rebecca, Vito W, Cantini, Liliana P, Abel, Ethan V, Pagano, Nicholas, Meggers, Eric, Mathew, Rahel, Krepler, Clemens, Izumi, Victoria, Fang, Bin, Koomen, John M, Messina, Jane L, Herlyn, Meenhard, Smalley, Keiran S M
• Format: Journal Article
• Language: English
• Published: London Elsevier Limited 01.12.2012
• ISSN: 0022-202X; 1523-1747
• DOI: 10.1038/jid.2012.237

This study addresses the role of glycogen synthase kinase (GSK)-3[beta] signaling in the tumorigenic behavior of melanoma. Immunohistochemical staining revealed GSK3[beta] to be focally expressed in the invasive portions of 12 and 33% of primary and metastatic melanomas, respectively. GSK3 inhibitors and small interfering RNA (siRNA) knockdown of GSK3[beta] were found to inhibit the motile behavior of melanoma cells in scratch wound, three-dimensional collagen-implanted spheroid, and modified Boyden chamber assays. Functionally, inhibition of GSK3[beta] signaling was found to suppress N-cadherin expression at the messenger RNA and protein levels, and was associated with decreased expression of the transcription factor Slug. Pharmacological and genetic ablation of GSK3[beta] signaling inhibited the adhesion of melanoma cells to both endothelial cells and fibroblasts and prevented transendothelial migration, an effect rescued by the forced overexpression of N-cadherin. A further role for GSK3[beta] signaling in invasion was suggested by the ability of GSK3[beta] inhibitors and siRNA knockdown to block phosphorylation of focal adhesion kinase (FAK) and increase the size of focal adhesions. In summary, we have, to our knowledge, demonstrated a previously unreported role for GSK3[beta] in modulating the motile and invasive behavior of melanoma cells through N-cadherin and FAK. These studies suggest the potential therapeutic utility of inhibiting GSK3[beta] in defined subsets of melanoma.