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GSK3β inhibition blocks melanoma cell/host interactions by downregulating N-cadherin expression and decreasing FAK

Jobin K John1, Kim H T Paraiso, Vito W Rebecca

  • 1Department of Molecular Oncology, The Moffitt Cancer Center and Research Institute, Tampa, Florida 33612, USA.

The Journal of Investigative Dermatology
|July 20, 2012
PubMed

Insights

Glycogen synthase kinase (GSK)-3β signaling drives melanoma cell movement and invasion. Inhibiting GSK3β reduces melanoma cell adhesion and migration, suggesting it as a potential therapeutic target.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Biology

Background:

  • Melanoma progression involves complex cellular behaviors like motility and invasion.
  • The precise molecular pathways regulating melanoma tumorigenesis require further elucidation.

Purpose of the Study:

  • To investigate the role of glycogen synthase kinase (GSK)-3β signaling in melanoma cell motility and invasion.
  • To identify downstream effectors and mechanisms through which GSK3β influences melanoma behavior.

Main Methods:

  • Immunohistochemical staining of GSK3β in primary and metastatic melanoma tissues.
  • In vitro assays (scratch wound, 3D collagen spheroid, Boyden chamber) to assess melanoma cell motility.
  • GSK3 inhibitors and small interfering RNA (siRNA) for GSK3β knockdown.
  • Analysis of N-cadherin and Slug expression at mRNA and protein levels.
  • Assays for melanoma cell adhesion to endothelial cells and fibroblasts, and transendothelial migration.
  • Assessment of focal adhesion kinase (FAK) phosphorylation and focal adhesion size.

Main Results:

  • GSK3β is focally expressed in invasive melanoma.
  • GSK3β inhibition or knockdown significantly reduced melanoma cell motility and invasion.
  • GSK3β signaling suppression decreased N-cadherin and Slug expression.
  • Inhibition of GSK3β impaired melanoma cell adhesion and transendothelial migration, an effect reversible by N-cadherin overexpression.
  • GSK3β inhibition blocked FAK phosphorylation and altered focal adhesion dynamics.

Conclusions:

  • GSK3β signaling plays a critical, previously unreported role in modulating melanoma cell motility and invasion.
  • The mechanisms involve regulation of N-cadherin, Slug, and FAK signaling pathways.
  • Targeting GSK3β may offer a therapeutic strategy for specific melanoma subtypes.

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