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• W1495280521 abstract "Fyn, a member of the Src family kinases (SFK), is an oncogene in murine epidermis and is associated with cell–cell adhesion turnover and induction of cell migration. Additionally, Fyn upregulation has been reported in multiple tumor types, including cutaneous squamous cell carcinoma (cSCC). Introduction of active H‐Ras(G12V) into the HaCaT human keratinocyte cell line resulted in upregulation of Fyn mRNA (200‐fold) and protein, while expression of other SFKs remained unaltered. Transduction of active Ras or Fyn was sufficient to induce an epithelial‐to‐mesenchymal transition in HaCaT cells. Inhibition of Fyn activity, using siRNA or the clinical SFK inhibitor Dasatinib, increased cell–cell adhesion and rapidly (5–60 min) increased levels of cortical F‐actin. Fyn inhibition with siRNA or Dasatinib also induced F‐actin in MDA‐MB‐231 breast cancer cells, which have elevated Fyn. F‐actin co‐localized with adherens junction proteins, and Dasatinib‐induced cell–cell adhesion could be blocked by Cytochalasin D, indicating that F‐actin polymerization was a key initiator of cell–cell adhesion through the adherens junction. Conversely, inhibiting cell–cell adhesion with low Ca 2+ media did not block Dasatinib‐induced F‐actin polymerization. Inhibition of the Rho effector kinase ROCK blocked Dasatinib‐induced F‐actin and cell–cell adhesion, implicating relief of Rho GTPase inhibition as a mechanism of Dasatinib‐induced cell–cell adhesion. Finally, topical Dasatinib treatment significantly reduced total tumor burden in the SKH1 mouse model of UV‐induced skin carcinogenesis. Together these results identify the promotion of actin‐based cell–cell adhesion as a newly described mechanism of action for Dasatinib and suggest that Fyn inhibition may be an effective therapeutic approach in treating cSCC. © 2014 Wiley Periodicals, Inc." @default.
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• W1495280521 date "2014-06-29" @default.
• W1495280521 modified "2023-10-16" @default.
• W1495280521 title "Targeting Fyn in Ras-transformed cells induces F-actin to promote adherens junction-mediated cell-cell adhesion" @default.
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• W1495280521 doi "https://doi.org/10.1002/mc.22190" @default.
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