Induction of terminal differentiation in melanoma cells on downregulation of beta-amyloid precursor protein.

The incidence of melanoma, the most aggressive type of skin cancer, is increasing dramatically, and an effective treatment for patients with advanced disease is as yet unavailable. Greater insight into the molecular features of primary and metastatic melanoma is required, particularly the identification of key regulatory genes that shield the tumor cells from terminal differentiation and apoptosis. The beta-amyloid precursor protein (APP) is a cell surface receptor and the transmembrane precursor of the Abeta-peptide, which has an important role in Alzheimer's disease. The study presented here provides evidence that APP is expressed at high levels in advanced-stage melanomas, and that the cells cleave APP and secrete sAPP. We show that blocking the expression of APP by RNA interference impairs the proliferation of metastatic melanoma cells and leads to their terminal and irreversible differentiation. In addition, suppressing APP expression in a metastatic melanoma cell line renders the cells susceptible to several chemotherapeutic agents. Targeting APP may thus constitute a new approach to the treatment of this disease.