RNF5, an endoplasmic reticulum (ER)
E3 ubiquitin ligase, participates to the ER-associated protein degradation guaranteeing the protein homeostasis. Depending on
tumor model tested, RNF5 exerts pro- or anti-
tumor activity. The aim of this study was to elucidate the controversial role of RNF5 in
neuroblastoma and
melanoma, two
neuroectodermal tumors of infancy and adulthood, respectively. RNF5 gene levels are evaluated in publicly available datasets reporting the gene expression profile of
melanoma and
neuroblastoma primary
tumors at diagnosis. The
therapeutic effect of Analog-1, an RNF5 pharmacological activator, was investigated on in vitro and in vivo
neuroblastoma and
melanoma models. In both
neuroblastoma and
melanoma patients the high expression of RNF5 correlated with a better prognostic outcome. Treatment of
neuroblastoma and
melanoma cell lines with Analog-1 reduced cell viability by impairing the
glutamine availability and energy metabolism through inhibition of F1Fo
ATP-synthase activity. This latter event led to a marked increase in oxidative stress, which, in turn, caused cell death. Similarly,
neuroblastoma- and
melanoma-bearing mice treated with Analog-1 showed a significant delay of
tumor growth in comparison to those treated with vehicle only. These findings validate RNF5 as an innovative drug target and support the development of Analog-1 in early phase clinical trials for
neuroblastoma and
melanoma patients.