Oleuropein downregulates MITF via direct PKA inhibition and ERK-mediated turnover in melanoma

The Microphthalmia-associated Transcription Factor (MITF) acts as a molecular rheostat in melanoma, governing the switch between proliferative and invasive phenotypic states. Since constitutive activation of the PKA-CREB axis drives high MITF levels to sustain tumor proliferation, targeting this pathway offers a promising therapeutic strategy. Here, we elucidate the mechanism by which oleuropein modulates MITF stability and expression in melanoma and normal melanocyte models. In B16F10 melanoma cells characterized by aberrant PKA signaling, oleuropein directly inhibited PKA catalytic activity, leading to reduced CREB phosphorylation and subsequent transcriptional suppression of MITF. Furthermore, oleuropein triggered ERK1/2 activation, accelerating MITF protein turnover. Consequently, oleuropein dismantled the hyper-proliferative transcriptional program through dual upstream and downstream regulatory mechanisms. Crucially, oleuropein reduced basal MITF levels in normal human melanocytes and effectively blunted MITF spikes induced by alpha-MSH or forskolin. This suggests that oleuropein functions as a potent inhibitor of the PKA-CREB axis, preventing pathological signaling amplification under both basal and hyperactivated conditions. In conclusion, by targeting PKA catalytic activity and promoting ERK-dependent degradation, oleuropein effectively attenuates aberrant MITF expression. These findings position oleuropein as a promising modulator of melanoma phenotypic plasticity with potential therapeutic applications.