Using in vitro NB and melanoma models, we show that treatment with the RNF5 activator Analog-1 reduces tumor cell proliferation and viability, decreases the glutamine and glutamate intracellular level, impairs energetic metabolism by inhibition of F1Fo ATP-synthase (ATP-synthase) activity, and increases apoptosis by promotion of oxidative stress. Here, RNF5 is linked to melanoma.