Search

Epidermal growth factor receptor (EGFR) is a causal factor in carcinoma, yet many carcinoma patients are resistant to EGFR inhibitors. Potential insight into this resistance stems from prior work that showed EGFR in normal epithelial cells docks to the extracellular domain of the plasma membrane proteoglycan syndecan-4 (Sdc4) engaged with α3β1 and α6β4 integrins. We now report that this receptor complex is modified by the recruitment of syndecan-2 (Sdc2), the Recepteur d'Origine Nantais (RON) tyrosine kinase, and the cellular signaling mediator Abelson murine leukemia viral oncogene homolog 1 (ABL1) in triple-negative breast carcinoma and head and neck squamous cell carcinoma, where it contributes to EGFR kinase-independent proliferation. Treatment with a peptide mimetic of the EGFR docking site in the extracellular domain of Sdc4 (called SSTN

Cosmetic practices that use skin-lightening agents to obtain desired skin tones or treat pigment abnormalities have been popular worldwide. However, the molecular and cellular mechanisms of these agents are still largely unknown. Here we identified a family of compounds, with the lead compound named A11, that exhibited strong pigment reduction in developing zebrafish embryos. The pigment inhibition lasted for several days and is effective both before and after melanogenesis. By comparison with several known skin-lightening compounds, A11 appeared to be more potent and caused slower pigment recovery after withdrawal. A11, however, did not inhibit tyrosinase or cause apoptosis in melanocytes. We further found that A11 suppressed proliferation in melanocytes and reduced the number of differentiated melanocytes by activating MAPK (mitogen-activated protein kinase) and Akt. Finally, A11 also caused melanin reduction in mammalian melanocytes. Together, A11 might be a potent skin-lightening agent with novel mechanisms.