Inhibition of p38/MK2 Signaling Prevents Vascular Invasion of Melanoma.

The Journal of investigative dermatology (2019-10-18)
Judith Wenzina, Silvio Holzner, Emmi Puujalka, Phil F Cheng, Agnes Forsthuber, Karin Neumüller, Klaudia Schossleitner, Beate M Lichtenberger, Mitchell P Levesque, Peter Petzelbauer
ABSTRACT

Melanoma cells can switch between distinct gene expression profiles, resulting in proliferative or invasive phenotypes. Signaling pathways involved in this switch were analyzed by gene expression profiling of a cohort of 22 patient-derived melanoma cell lines. CDH1 negativity was identified as a surrogate marker for the invasive phenotype. CDH1 expression could be turned on and off by modulating activity of p38 or its downstream target MK2, suggesting that this pathway controls melanoma progression. Mechanistically, MK2 inhibition prevented melanoma-induced vascular barrier disruption, reduced the expression of PODXL and DEL-1, and prevented vascular dissemination in vivo. PODXL and DEL-1 expression in patients with melanoma were associated with poor survival and thus can be used as prognostic markers. Downstream targets of MK2 may thus serve as candidate therapeutics.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Protease Inhibitor Cocktail, for use with mammalian cell and tissue extracts, DMSO solution
Sigma-Aldrich
Phosphatase Inhibitor Cocktail 2, aqueous solution (dark coloration may develop upon storage, which does not affect the activity)
Sigma-Aldrich
Phosphatase Inhibitor Cocktail 3, DMSO solution
Sigma-Aldrich
Monoclonal Anti-β-Actin antibody produced in mouse, clone AC-74, purified immunoglobulin, buffered aqueous solution
Sigma-Aldrich
Arg-Gly-Asp, ≥97% (TLC)
Sigma-Aldrich
Monoclonal Anti-CDH1 antibody produced in mouse, clone 67A4, purified immunoglobulin, buffered aqueous solution